LITERATURE REVIEW



The time course of changes in brown adipose tissue fat fraction during cooling and warming in adult malesThe time course of changes in brown adipose tissue fat fraction during cooling and warming in adult malesBy Stephan Mark Oreskovich, B.HSc.A Thesis Submitted to the School of Graduate Studies in Partial Fulfilment of the Requirements for the Degree Master of SciencesMcMaster University ? Copyright by Stephan Mark Oreskovich, July 2018Master of Science (Department Medical Sciences, 2018)McMaster University, Hamilton, OntarioTITLE: The time course of changes in brown adipose tissue fat fraction during cooling and warming in adult malesAUTHOR: Stephan Mark Oreskovich, B.HSc. (McMaster University) SUPERVISOR: Dr. Katherine Morrison COMMITTEE: Dr. Katherine Morrison, Dr. Gregory Steinberg and Dr. Zubin PunthakeeNUMBER OF PAGES: xii, 101ABSTRACTBackground: Brown adipose tissue (BAT) preferentially oxidizes stored triglycerides (TAGs) to generate heat during acute exposure to cold. However, the time course of its activation is not well described as we are currently limited to BAT measurements before and after an acute stimulus. Magnetic resonance imaging (MRI) is a preferred modality to uncover such evidence, as it estimates TAG content via fat fraction (FF), and permits repeat scans in the same subject. As such, serial FF measurements in a defined BAT region of interest during a uniform whole-body temperature challenge is warranted.Objectives: The first objective of this study was to assess the pattern of change in supraclavicular (SCV) BAT and posterior neck subcutaneous adipose tissue (SAT; a region with an unestablished role in non-shivering thermogenesis) FF during a mild cold exposure in adult males. The second objective was to evaluate if indices of body composition were related to the pattern of cold-induced change in SCV BAT FF. The final objective was to assess the influence of warming immediately following cooling on these changes. Methods: Twelve males between the ages of 19 and 28 were recruited to this cross-sectional study. Users of tobacco, nicotine, and/or alcohol, those with contraindications for magnetic resonance imaging (MRI), and diseases, surgeries, and/or medications associated with thermogenesis were excluded. There were two study visits in total. During the initial visit, anthropometric measurements were carried out in triplicate (i.e. height and weight to determine body mass index (BMI), and body composition measurements (i.e. % body total fat and lean mass (kg)) were obtained using Dual Emission X-Ray Absorptiometry. Within 30 days of this initial visit, subjects attended a time course MRI session. At this visit, participants underwent standardized cold (3-hours at 18°C) and subsequent warm (30 minutes at 32°C) exposures using a water-perfused suit while lying in a 3 Tesla MRI scanner, and the temperature of the water entering and leaving the suit was recorded throughout. FF in the SCV region and posterior neck SAT was measured at defined intervals during both temperature challenges. Separate time course plots of the mean reduction in FF from baseline were constructed for the cooling and warming phases. For the first objective, the rate and magnitude of FF changes in SCV BAT and posterior neck SAT over defined time intervals were determined through calculations of slope and area under the curve (AUC), respectively. Identification of the earliest point of change from baseline, and the point at which changes were no longer different from those measured after 3 hours of cooling, were accomplished through paired comparisons using a random-slope linear mixed model with measures at 0 minutes and 180 minutes used as the reference values, respectively. A random-intercept multilevel regression model was used to define the cold-induced change in FF over time. For the second objective, a Spearman rank-order correlation assessed the association between indices of body composition (i.e. BMI and % total body fat) and indices of BAT activity (i.e. AUC and FF reduction) at time points of interest as identified by objective 1.Results: The mean±SD of BMI, LMI, and % total body fat were 24.7±2.8kg/m2, 17.6±1.6kg/m2 and 25.0±7.4%, respectively. Seven of the twelve subjects completed three hours of cold exposure (58.3%), and a further five endured at least one hour. A significant cold-induced reduction in SCV BAT FF was detected at 10 minutes following the onset of cold exposure (mean difference = -1.6%; p=0.005), and changes in FF beyond 30 minutes of cooling were similar to those measured after three hours (p<0.05). Meanwhile, the posterior neck SAT did not experience significant cold-induced changes in FF. A novel attempt at identifying a quadratic model to predict one’s BAT-specific response to a cold challenge was carried out, and the intercept, time, time2, and intraclass correlation coefficient (i.e. parameters which described the relationship between FF and time) were highly significant (p<0.001). Although every participant had a measurable decline in FF, those with a higher BMI and % body fat had a smaller magnitude of change throughout the time course. In particular, a strong negative correlation between BMI and AUC FF decline existed as soon as 10 minutes following the onset of cold (rho=-0.786), indicating that those with a lower BMI had a larger magnitude of change in SCV BAT FF at this point. Finally, warming did not visually influence the trajectory of SCV BAT FF.Limitations: Only seven of the twelve participants completed the full 180 minutes of cold exposure, which further limited the already low statistical power of this study. Moreover, complementary measures of BAT activity, such as energy expenditure, and objective measurements of shivering, such as electromyography, could not be evaluated.Conclusions: These findings suggest that significant cold-induced changes in BAT FF occur much sooner than three hours. Thus, a shorter duration of cold exposure may be considered in future studies using MRI to detect BAT activity, as this could increase the feasibility of gathering larger and younger sample populations.ACKNOWLEDGEMENTSI would first like to thank my thesis supervisor, Dr. Katherine Morrison, for her expertise and undying support throughout the course of my M.Sc. studies. I truly appreciated her patience, approachability, encouragement to persevere through self-efficacy, and confidence in me as a trainee. She helped to ignite within me a curiosity and passion for research that will continue to fuel my professional aspirations and endeavors. In addition to my advisor, I would like to thank the rest of my thesis committee – Dr. Gregory Steinberg and Dr. Zubin Punthakee – for their insightful comments and through-provoking questions. Having such a diverse team of professionals guide me through this process encouraged me to view my own research with both a clinical and basic science perspective. I would also like to acknowledge Norm Konyer, Dr. Michael Noseworthy, Dr. Nina Singh, Dr. Francois Haman, and Dr. Denis Blondin for their assistance in developing this project. My sincere thanks also goes to Dr. Noori Akhtar-Danesh for generously spending his own time to guide me through complex statistical concepts.I thank my Research Coordinator, Elizabeth Gunn, for keeping me on track and providing insight when immediately sought. Further, my sincere gratitude goes out to all of my fellow lab mates, both past and present, who were both directly and indirectly involved with this project: Dr. Basma Ahmed, Frank Ong, Emily Hutchings, Prasiddha Parthasarathy, Efrah Yousuf, Riddhi Desai, Vivian Vaughan Williams, Kelly Bradbury, Jen Li, Marilia Carvalho, April Liu, and Stephanie Kim. Thank you for all of the stimulating discussions and fun times over the last two years.Importantly, I would like to thank my brave participants for battling the cold. Also, thank you to Denise Wedge for taking the time to organize all of my practice presentations and committee meetings. Last but certainly not least, I would like to thank my wonderful parents and girlfriend for constantly annoying me with rudimentary questions that ultimately helped me to develop a more holistic understanding of my project. Their enthusiasm and unconditional love continued to propel me when things were not going as planned.TABLE OF CONTENTS TOC \o "1-3" \h \z \u 1LITERATURE REVIEW PAGEREF _Toc519069242 \h 11.1Introduction to Brown Adipose Tissue PAGEREF _Toc519069243 \h 21.1.1Background PAGEREF _Toc519069244 \h 21.1.2Mechanism of Non-Shivering Thermogenesis PAGEREF _Toc519069245 \h 21.2Fuels for BAT Non-Shivering Thermogenesis PAGEREF _Toc519069246 \h 41.2.1Lipids PAGEREF _Toc519069247 \h 41.2.2Glucose PAGEREF _Toc519069248 \h 51.3Factors associated with brown adipose tissue presence and activity PAGEREF _Toc519069249 \h 51.3.1Age PAGEREF _Toc519069250 \h 61.3.2Sex PAGEREF _Toc519069251 \h 61.3.3Body Composition PAGEREF _Toc519069252 \h 61.3.4Environmental Factors PAGEREF _Toc519069253 \h 71.4BAT imaging PAGEREF _Toc519069254 \h 81.4.118F-FDG PET/CT PAGEREF _Toc519069255 \h 81.4.2MRI Fat Fraction PAGEREF _Toc519069256 \h 91.4.3MRI T2* PAGEREF _Toc519069257 \h 91.4.4Strengths and Limitations Of MRI PAGEREF _Toc519069258 \h 101.5Current state of the literature in humans PAGEREF _Toc519069259 \h 111.5.1BAT Time Course Evidence to Date PAGEREF _Toc519069260 \h 112STUDY RATIONALE AND OBJECTIVES PAGEREF _Toc519069261 \h 142.1Rationale and Significance PAGEREF _Toc519069262 \h 152.2Overarching Purpose PAGEREF _Toc519069263 \h 152.3Objectives and Hypotheses PAGEREF _Toc519069264 \h 152.3.1Objectives PAGEREF _Toc519069265 \h 152.3.2Hypotheses PAGEREF _Toc519069266 \h 163METHODS PAGEREF _Toc519069267 \h 173.1Study Design and Population PAGEREF _Toc519069268 \h 183.2Study Visits PAGEREF _Toc519069269 \h 193.2.1Initial Visit PAGEREF _Toc519069270 \h 193.2.2Time Course MRI Session PAGEREF _Toc519069271 \h 193.3Study Procedures PAGEREF _Toc519069272 \h 203.3.1Cold and Warm Exposures PAGEREF _Toc519069273 \h 203.3.2Primary Outcome Measure PAGEREF _Toc519069274 \h 213.3.3Anthropometrics PAGEREF _Toc519069275 \h 233.3.4Body composition PAGEREF _Toc519069276 \h 243.3.5Environmental Factors PAGEREF _Toc519069277 \h 243.4Statistical Analysis PAGEREF _Toc519069278 \h 244RESULTS PAGEREF _Toc519069279 \h 264.1Project Recruitment PAGEREF _Toc519069280 \h 274.2Participant Characteristics PAGEREF _Toc519069281 \h 274.3Data collection and analysis summary PAGEREF _Toc519069282 \h 284.4Identifying the time course of change in SCV BAT FF with cooling PAGEREF _Toc519069283 \h 294.5Investigating if participant characteristics are related to the pattern of cold-induced change PAGEREF _Toc519069284 \h 344.6Identifying the time course of change in SCV BAT FF with warming PAGEREF _Toc519069285 \h 365DISCUSSION PAGEREF _Toc519069286 \h 385.1Objective 1: Time Course of Change in SCV BAT FF over cooling PAGEREF _Toc519069287 \h 395.2Objective 2: Relationship between indices of BAT activity at time points of interest and covariates of BAT activity. PAGEREF _Toc519069288 \h 485.3Objective 3: Time course of FF during warming PAGEREF _Toc519069289 \h 526CONCLUSION PAGEREF _Toc519069290 \h 546.1Summary of Findings PAGEREF _Toc519069291 \h 556.2Limitations and Recommendations for Future Studies PAGEREF _Toc519069292 \h 556.3Next Steps PAGEREF _Toc519069293 \h 587APPENDIX PAGEREF _Toc519069294 \h 607.1Supplementary Material (Introduction) PAGEREF _Toc519069295 \h 607.2Supplementary Material (Methods) PAGEREF _Toc519069296 \h 667.2.1Exclusion Criteria PAGEREF _Toc519069297 \h 667.2.2List of serotonergic foods PAGEREF _Toc519069298 \h 707.2.3Visit Timelines PAGEREF _Toc519069299 \h 707.2.4MRI Parameters PAGEREF _Toc519069300 \h 717.2.5Stepwise procedure for image segmentation PAGEREF _Toc519069301 \h 727.2.6Pairwise comparisons for identifying time points of interest PAGEREF _Toc519069302 \h 747.2.7Quadratic Modeling of SCV BAT FF PAGEREF _Toc519069303 \h 757.3Supplementary Material (Results) PAGEREF _Toc519069304 \h 767.3.1Individual Time Course Plots (FF reduction) PAGEREF _Toc519069305 \h 767.3.2Individual Time Course Plots (Absolute Change) PAGEREF _Toc519069306 \h 787.3.3Time course of change in T2* during Cooling PAGEREF _Toc519069307 \h 817.3.4Time course of change among individuals who completed the full duration of cooling (n=7) PAGEREF _Toc519069308 \h 827.3.5Tabular Output from the Pairwise Comparisons PAGEREF _Toc519069309 \h 837.3.6Time course of change in posterior neck SAT FF PAGEREF _Toc519069310 \h 847.3.7Investigating if participant characteristics are related to the pattern of cold-induced change PAGEREF _Toc519069311 \h 857.3.8Time course of T2* reduction during warming PAGEREF _Toc519069312 \h 887.4Supplementary Material (Discussion) PAGEREF _Toc519069313 \h 898BIBLIOGRAPHY PAGEREF _Toc519069314 \h 90LIST OF FIGURES TOC \c "Figure" Figure 1 - Calculation of AUC PAGEREF _Toc517294845 \h 23Figure 2 - Calculation of slope PAGEREF _Toc517294846 \h 23Figure 3 - Recruitment Flow Chart for the GETBAT Timecourse Substudy PAGEREF _Toc517294847 \h 27Figure 4 – Changes in SCV BAT FF during cooling. PAGEREF _Toc517294848 \h 30Figure 5 - Graphical representation of the quadratic model PAGEREF _Toc517294849 \h 32Figure 6 – Changes posterior neck SAT FF during cooling PAGEREF _Toc517294850 \h 33Figure 7 - Individual patterns of FF reduction among those who completed the full cooling protocol PAGEREF _Toc517294851 \h 34Figure 8 – Relationships between BMI and % body fat and indices of BAT activity. PAGEREF _Toc517294852 \h 35Figure 9 - Time course of FF reduction during warming in the SCV BAT. Data are mean±SD. PAGEREF _Toc517294853 \h 36Figure 10 - Figure 6 from Hu et al. (2013) PAGEREF _Toc517294854 \h 60Figure 11 – Initial Visit (McMaster University Medical Centre) PAGEREF _Toc517294855 \h 70Figure 12 – Time Course Visit (St. Joseph's Healthcare Hamilton) PAGEREF _Toc517294856 \h 70Figure 13 – Visual representation of the time course MRI session71Figure 14 - Axial Slice of the Lower Cervical Region PAGEREF _Toc517294857 \h 74Figure 15 - T2* reduction during cooling PAGEREF _Toc517294858 \h 81Figure 16 – Changes in FF among those who completed the full 3-hour exposure. PAGEREF _Toc517294859 \h 82Figure 17 - Jitter plots of ambient and environmental temperature PAGEREF _Toc517294860 \h 85Figure 18 - Jitter plots of indices of body composition. PAGEREF _Toc517294861 \h 86Figure 19 - Jitter pots of AUC during the first hour of cooling85Figure 20 - Time course of Spearman Correlation Coefficients87Figure 21 - T2* reduction during warming PAGEREF _Toc517294863 \h 88Figure 22 - Proposed model for time course of fuel use during BAT activation88LIST OF TABLES TOC \c "Table" Table 1 - Criteria and conditions used in the study PAGEREF _Toc517295252 \h 18Table 2 - Descriptives for the GETBAT Timecourse Substudy PAGEREF _Toc517295253 \h 27Table 3 - MRI Acquisition and Analysis Summary PAGEREF _Toc517295254 \h 28Table 4 - Summary of individual cold-induced changes in SCV BAT FF PAGEREF _Toc517295255 \h 29Table 5 - Random-effects multilevel regression model PAGEREF _Toc517295256 \h 31Table 6 - Rate of change in FF from 0-60 minutes of cold exposure PAGEREF _Toc517295257 \h 43Table 7 - Time Course Measurements (Humans) PAGEREF _Toc517295258 \h 60Table 8 - Time Course Measurements (Animals) PAGEREF _Toc517295259 \h 63Table 9 - List of excluded medications PAGEREF _Toc517295260 \h 66Table 10 - List of excluded conditions PAGEREF _Toc517295261 \h 69Table 11 - MRI protocol parameters for IDEAL-IQ PAGEREF _Toc517295262 \h 71Table 12 - Linear mixed model selection summary PAGEREF _Toc517295263 \h 74Table 13 - Pairwise comparisons using LMM with 0 minutes as the reference (SCV BAT) PAGEREF _Toc517295264 \h 83Table 14 - Pairwise comparisons using LMM with 180 minutes as the reference (SCV BAT) PAGEREF _Toc517295265 \h 83Table 15 - Summary of individual cold-induced changes in posterior neck SAT FF PAGEREF _Toc517295266 \h 84Table 16 - Pairwise comparisons using LMM with 0 minutes as the reference (posterior neck SAT) PAGEREF _Toc517295267 \h 84Table 17 - Comparing those who completed the full duration of cooling and those who did not. PAGEREF _Toc517295268 \h 87Table 18 - P-values corresponding to each Spearman rho value.87LIST OF ABBREVIATIONS18F-FDG: 18-fluorodeoxy glucose1H-MRS: proton magnetic resonance spectroscopyATP: adenosine triphosphateAUC: area under the curveBAT: brown adipose tissueBMI: body mass indexBOLD: blood-oxygen-level dependentDXA: dual emission x-ray absorptiometryEE: energy expenditure EMG: electromyography FF: fat-fractionFFA: free fatty acidsfMRI: functional MRI iBAT: interscapular brown adipose tissueIDEAL: iterative decomposition with echo-asymmetry and least squares estimationIQR: interquartile rangeIRT: infrared thermographyLMI: lean mass indexLMM: linear mixed modelLPL: lipoprotein lipase MRI: magnetic resonance imagingMST: mean skin temperatureNE: norepinephrineNST: non-shivering thermogenesis PDFF: proton-density fat-fraction PET/CT: positron emission tomography – computer tomographyROI: region of interest SAT: subcutaneous adipose tissueSCV: supraclavicular fossaSD: standard deviationSNS: sympathetic nervous systemTAGs: triglycerides TRL: triglyceride-rich lipoprotein UCP1: uncoupling protein-1WAT: white adipose tissueLITERATURE REVIEWIntroduction to Brown Adipose TissueBackgroundBrown adipose tissue (BAT) contributes uniquely to whole-body metabolic homeostasis by catabolizing available substrates to generate heatADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00084","ISBN":"1664-2392 (Electronic)\\r1664-2392 (Linking)","ISSN":"1664-2392","PMID":"22654830","abstract":"Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.","author":[{"dropping-particle":"","family":"Festuccia","given":"William T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanchard","given":"Pierre-Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshaies","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"December","issued":{"date-parts":[["2011"]]},"page":"1-6","title":"Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ.","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1. Historically, the function and physiological significance of BAT has been discussed in the context of rodents and hibernating animals. Its potential relevance to humans was largely overlooked until a symmetrical depot in the supraclavicular (SCV) area of adult oncology patients undergoing fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) was identified serendipitously as metabolically active BATADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00691.2006.","author":[{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bengtsson","given":"Tore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology Endocrinology Metabolism","id":"ITEM-1","issued":{"date-parts":[["2007"]]},"page":"444-452","title":"Unexpected evidence for active brown adipose tissue in adult humans","type":"article-journal","volume":"293"},"uris":[""]}],"mendeley":{"formattedCitation":"²","plainTextFormattedCitation":"2","previouslyFormattedCitation":"²"},"properties":{"noteIndex":0},"schema":""}2. In subsequent investigations using PET/CT, BAT (i.e. presence and activity) was higher in paediatric populations (~50%) compared to adults (~5%)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/pr.2012.141","ISBN":"1530-0447","ISSN":"1530-0447","PMID":"23090604","abstract":"Brown adipose tissue (BAT) was thought to disappear after infancy. Recent findings of BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggest that BAT is more prevalent in children than in adults and that its activation during adolescence is associated with significantly lower gains in weight and adiposity. Data also show that pediatric patients with metabolically active BAT on PET/CT examinations have significantly greater muscle volume than patients without identifiable BAT. Both the activity and the amount of BAT increase during puberty. The magnitude of the increase is higher in boys as compared with girls and is closely related to gains in muscle volume. Hence, concurrent with the gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between brown adipocytes, white adipocytes, and myocytes. In this review, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children.","author":[{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"3-9","title":"Relevance of brown adipose tissue in infancy and adolescence.","type":"article-journal","volume":"73"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}3. A potential explanation for this is the evolution of “classic” BAT (i.e. homogenous in morphology) from interscapular depots in infants to primarily the SCV in adults, with smaller amounts detected in the mediastinal, paravertebral, suprarenal, and upper abdominal regionsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00247-010-1925-y","ISBN":"1432-1998 (Electronic)\\n0301-0449 (Linking)","ISSN":"03010449","PMID":"21161205","abstract":"Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET.","author":[{"dropping-particle":"","family":"Hong","given":"Terence S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shammas","given":"Amer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Charron","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2011"]]},"page":"759-768","title":"Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}4. BAT activity is facultative and its evolutionary function is to maintain core body temperature via non-shivering thermogenesis (NST)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1749-6632.2010.05905.x","ISBN":"1749-6632 (Electronic)\\r0077-8923 (Linking)","ISSN":"17496632","PMID":"21375707","abstract":"The presence of active brown adipose tissue in adult humans has been recognized in general physiology only since 2007. The intervening three years established that the depots originally observed by (18)F-fluoro-deoxy-glucose positron emission tomography ({FDG} {PET}) scanning techniques really are brown adipose tissue depots because they are enriched for uncoupling protein 1 ({UCP}1). Reports of low apparent prevalence of brown adipose tissue based on retrospective studies of hospital records of {FDG} {PET} scans markedly underestimate true prevalence because such studies only reflect acute activity state; consequently, such retrospective studies cannot be conclusively analysed for factors influencing activity and amount of brown adipose tissue. Dedicated studies show that the true prevalence is 30-100%, depending on cohort. Warm temperature during the investigation-as well as adrenergic antagonists-inhibit tissue activity. There is probably no sexual dimorphism in the prevalence of brown adipose tissue. Outdoor temperature may affect the amount of brown adipose tissue, and the amount is negatively correlated with age and obesity. The presence of brown adipose tissue is associated with cold-induced nonshivering thermogenesis, and the tissue may be a major organ for glucose disposal. The decline in brown adipose tissue amount with increasing age may account for or aggravate middle-age obesity. Maintained activation of brown adipose tissue throughout life may thus protect against obesity and diabetes.","author":[{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bengtsson","given":"Tore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of the New York Academy of Sciences","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"page":"20-36","title":"Three years with adult human brown adipose tissue.","type":"article-journal","volume":"1212"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵","plainTextFormattedCitation":"5","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}5. NST is a physiological phenomenon whereby oxidative phosphorylation on the inner mitochondrial membrane is separated from adenosine triphosphate (ATP) synthesis via uncoupling protein 1 (UCP1). In short, UCP1 shuttles protons liberated during fuel oxidation across the inner mitochondrial membrane and the consequential loss of potential energy produces heat as a by-productADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2015.00156","ISBN":"1664-2392","ISSN":"16642392","PMID":"26528238","abstract":"Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized.","author":[{"dropping-particle":"","family":"Porter","given":"Craig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chondronikola","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sidossis","given":"Labros S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"OCT","issued":{"date-parts":[["2015"]]},"page":"1-8","title":"The therapeutic potential of brown adipocytes in humans","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷","plainTextFormattedCitation":"7","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}7. The physiological process of substrate use during NST will be discussed in Section 1.2 below.Mechanism of Non-Shivering ThermogenesisThe sympathetic nervous system (SNS) responds to a stimulus by secreting norepinephrine (NE), which preferentially binds to the β3 subset of adrenergic receptors on the surface of BAT cellsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. A subsequent signaling cascade increases the activity of intracellular lipases, which function to release free fatty acids (FFAs) from stored triglyceride (TAGs)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. The resultant effect is twofold – FFAs are both the fuel for beta oxidation and the “switch” that activates UCP1 (the hallmark of NST in humans)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00691.2006.","author":[{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bengtsson","given":"Tore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology Endocrinology Metabolism","id":"ITEM-1","issued":{"date-parts":[["2007"]]},"page":"444-452","title":"Unexpected evidence for active brown adipose tissue in adult humans","type":"article-journal","volume":"293"},"uris":[""]}],"mendeley":{"formattedCitation":"²","plainTextFormattedCitation":"2","previouslyFormattedCitation":"²"},"properties":{"noteIndex":0},"schema":""}2. As respiration is uncoupled from ATP synthesis, the energy produced from the combustion of these substrates is released as a functional byproduct – heatADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6.BAT Stimulation in HumansCold exposure is the most potent and clinically relevant stimulator of BAT in humans, and therefore has been widely utilized to date. The physiological connection between cold and NST involves efficient communication between temperature sensors in the periphery and the SNS, resulting in β3-adrenergic receptor activationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.beem.2016.08.003","ISSN":"1521690X","PMID":"27697214","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Best Practice & Research Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"537-547","publisher":"Elsevier Ltd","title":"Activation and recruitment of brown adipose tissue by cold exposure and food ingredients in humans","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸","plainTextFormattedCitation":"8","previouslyFormattedCitation":"⁸"},"properties":{"noteIndex":0},"schema":""}8. Currently, however, there is no cold stimulation protocol that defines an optimal temperature and duration for maximal NSTADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e., close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) imaging. Dynamic imaging provides quantitative information about glucose uptake rates, whereas static imaging reflects overall BAT glucose uptake, localization, and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET image, leading to spillover. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [18F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the “fixed volume” methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like magnetic resonance imaging or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"A. A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"M. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"W. D.","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"R103-R113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹","plainTextFormattedCitation":"9","previouslyFormattedCitation":"⁹"},"properties":{"noteIndex":0},"schema":""}9. The implications of this lack of consistency will be discussed in Section 1.5 below.Whether the exposure is acute or prolonged, there are quantifiable metabolic benefits to BAT activation and recruitment. Hanssen et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db15-1372","ISSN":"1939327X","PMID":"26718499","abstract":"Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.","author":[{"dropping-particle":"","family":"Hanssen","given":"Mark J W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"Van Der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jardon","given":"Kelly M C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaart","given":"Gert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"Van","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2016"]]},"page":"1179-1189","title":"Short-term cold acclimation recruits brown adipose tissue in obese humans","type":"article-journal","volume":"65"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰","plainTextFormattedCitation":"10","previouslyFormattedCitation":"¹⁰"},"properties":{"noteIndex":0},"schema":""}10 examined the effects of a 10-day cold acclimation period (2-6 hours at 14-15°C) in ten obese adults and observed increased 18F-FDG uptake in BAT and skeletal muscle, both of which contribute positively to whole-body glucose homeostasis. Furthermore, Blondin et al. ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11 used a 3 hour exposure at 18°C and in addition to showing similar increases in BAT-specific glucose uptake, they found a significant association between plasma FFA appearance rate (i.e. due to white adipose tissue (WAT) lipolysis) and BAT oxidative metabolism. Although this suggests a link between BAT activity and heightened glucose and lipid clearance, results of this study are limited by the use of lean and healthy young males.The metabolic importance of prolonged BAT activation has been most evident in studies using animal models ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2015.09.007","ISBN":"1932-7420 (Electronic)\r1550-4131 (Linking)","ISSN":"19327420","PMID":"26445512","abstract":"Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.","author":[{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"546-559","publisher":"Elsevier Inc.","title":"Brown and beige fat: Physiological roles beyond heat generation","type":"article-journal","volume":"22"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/nm.2297","ISBN":"1546-170X (Electronic)\\r1078-8956 (Linking)","ISSN":"1546-170X","PMID":"21258337","abstract":"Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.","author":[{"dropping-particle":"","family":"Bartelt","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruns","given":"O T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reimer","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohenberg","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ittrich","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peldschus","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaul","given":"M G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tromsdorf","given":"U I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weller","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waurisch","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eychmuller","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordts","given":"P L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rinninger","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruegelmann","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freund","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkel","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heeren","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nat Med","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2011"]]},"page":"200-205","publisher":"Nature Publishing Group","title":"Brown adipose tissue activity controls triglyceride clearance","type":"article-journal","volume":"17"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1172/JCI62308DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"1558-8238","PMID":"23221344","abstract":"Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.","author":[{"dropping-particle":"","family":"Stanford","given":"K I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Middelbeek","given":"R J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Townsend","given":"K L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"An","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nygaard","given":"E B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hitchcox","given":"K M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markan","given":"K R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakano","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirshman","given":"M F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goodyear","given":"L J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Clin Invest","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2013"]]},"page":"215-223","title":"Brown adipose tissue regulates glucose homeostasis and insulin sensitivity","type":"article-journal","volume":"123"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1038/nature07182","ISBN":"1476-4687 (Electronic)","ISSN":"1476-4687","PMID":"18719582","abstract":"Brown fat can increase energy expenditure and protect against obesity through a specialized program of uncoupled respiration. Here we show by in vivo fate mapping that brown, but not white, fat cells arise from precursors that express Myf5, a gene previously thought to be expressed only in the myogenic lineage. We also demonstrate that the transcriptional regulator PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) controls a bidirectional cell fate switch between skeletal myoblasts and brown fat cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation. Conversely, ectopic expression of PRDM16 in myoblasts induces their differentiation into brown fat cells. PRDM16 stimulates brown adipogenesis by binding to PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) and activating its transcriptional function. Finally, Prdm16-deficient brown fat displays an abnormal morphology, reduced thermogenic gene expression and elevated expression of muscle-specific genes. Taken together, these data indicate that PRDM16 specifies the brown fat lineage from a progenitor that expresses myoblast markers and is not involved in white adipogenesis.","author":[{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bjork","given":"Bryan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yang","given":"Wenli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chin","given":"Sherry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuang","given":"Shihuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scimè","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Devarakonda","given":"Srikripa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Conroe","given":"Heather M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erdjument-Bromage","given":"Hediye","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tempst","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rudnicki","given":"Michael a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beier","given":"David R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature","id":"ITEM-4","issue":"7207","issued":{"date-parts":[["2008"]]},"page":"961-7","title":"PRDM16 controls a brown fat/skeletal muscle switch.","type":"article-journal","volume":"454"},"uris":[""]}],"mendeley":{"formattedCitation":"^12–15","plainTextFormattedCitation":"12–15","previouslyFormattedCitation":"^12–15"},"properties":{"noteIndex":0},"schema":""}12–15. For instance, knockout mice for PRDM16 or its coactivator EHMT1 (i.e. genes that stimulate BAT) develop concomitant obesity and hepatic steatosisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2015.09.007","ISBN":"1932-7420 (Electronic)\r1550-4131 (Linking)","ISSN":"19327420","PMID":"26445512","abstract":"Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.","author":[{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"546-559","publisher":"Elsevier Inc.","title":"Brown and beige fat: Physiological roles beyond heat generation","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12. Further, Bartelt et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nm.2297","ISBN":"1546-170X (Electronic)\\r1078-8956 (Linking)","ISSN":"1546-170X","PMID":"21258337","abstract":"Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.","author":[{"dropping-particle":"","family":"Bartelt","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruns","given":"O T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reimer","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohenberg","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ittrich","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peldschus","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaul","given":"M G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tromsdorf","given":"U I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weller","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waurisch","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eychmuller","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordts","given":"P L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rinninger","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruegelmann","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freund","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkel","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heeren","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nat Med","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2011"]]},"page":"200-205","publisher":"Nature Publishing Group","title":"Brown adipose tissue activity controls triglyceride clearance","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³","plainTextFormattedCitation":"13","previouslyFormattedCitation":"¹³"},"properties":{"noteIndex":0},"schema":""}13 used a cold-activated mouse model to show that BAT activity can result in improved plasma TAG clearance through local lipoprotein lipase (LPL) activity. Complementary to this finding, murine models with BAT transplantation into abdominal visceral adipose tissue have displayed significantly improved glucose tolerance and insulin sensitivityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI62308DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"1558-8238","PMID":"23221344","abstract":"Brown adipose tissue (BAT) is known to function in the dissipation of chemical energy in response to cold or excess feeding, and also has the capacity to modulate energy balance. To test the hypothesis that BAT is fundamental to the regulation of glucose homeostasis, we transplanted BAT from male donor mice into the visceral cavity of age- and sex-matched recipient mice. By 8-12 weeks following transplantation, recipient mice had improved glucose tolerance, increased insulin sensitivity, lower body weight, decreased fat mass, and a complete reversal of high-fat diet-induced insulin resistance. Increasing the quantity of BAT transplanted into recipient mice further improved the metabolic effects of transplantation. BAT transplantation increased insulin-stimulated glucose uptake in vivo into endogenous BAT, white adipose tissue (WAT), and heart muscle but, surprisingly, not skeletal muscle. The improved metabolic profile was lost when the BAT used for transplantation was obtained from Il6-knockout mice, demonstrating that BAT-derived IL-6 is required for the profound effects of BAT transplantation on glucose homeostasis and insulin sensitivity. These findings reveal a previously under-appreciated role for BAT in glucose metabolism.","author":[{"dropping-particle":"","family":"Stanford","given":"K I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Middelbeek","given":"R J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Townsend","given":"K L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"An","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nygaard","given":"E B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hitchcox","given":"K M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markan","given":"K R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakano","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirshman","given":"M F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Y H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goodyear","given":"L J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Clin Invest","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"215-223","title":"Brown adipose tissue regulates glucose homeostasis and insulin sensitivity","type":"article-journal","volume":"123"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴","plainTextFormattedCitation":"14","previouslyFormattedCitation":"¹⁴"},"properties":{"noteIndex":0},"schema":""}14. Therefore, prolonged stimulation of BAT can potentially rescue an obese phenotype and its associated negative metabolic comorbidities. Fuels for BAT Non-Shivering ThermogenesisFuel selection during BAT NST is specific despite a diverse pool of available substrates. Ultimately, two macromolecules which are readily available throughout the human body are utilized – lipids and to a lesser extent, glucose.LipidsOur current understanding is that BAT preferentially utilizes FFA stored within its many intracellular lipid droplets to fuel NST. In exposing rats to an environmental temperature of 6°C, Cameron and SmithADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Cameron","given":"Ivan L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Robert E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Cell Biology","id":"ITEM-1","issue":"23","issued":{"date-parts":[["1964"]]},"page":"89-100","title":"Cytological Responses of Brown Fat Tissue in Cold-Exposed Rats","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁶","plainTextFormattedCitation":"16","previouslyFormattedCitation":"¹⁶"},"properties":{"noteIndex":0},"schema":""}16 observed a depletion of multilocular lipid material within the interscapular BAT (iBAT), a prominent depot in murine models, during the early periods of cold exposure (i.e. within 6 hours). A similar depletion of BAT intracellular TAG content was realized during necropsy of newborn infant and adult humans who died from hypothermiaADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Aherne","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hull","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Pathol Bacteriol","id":"ITEM-1","issue":"1","issued":{"date-parts":[["1966"]]},"page":"223-234","title":"Brown adipose tissue and heat production in the newborn infant","type":"article-journal","volume":"91"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁷","plainTextFormattedCitation":"17","previouslyFormattedCitation":"¹⁷"},"properties":{"noteIndex":0},"schema":""}17. These early investigations sparked an interest among the research community, who have since used healthy human subjects and specialized imaging modalities to solidify this principle. For example, Ouellet et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISSN":"1558-8238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"note":"NULL","title":"Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans","type":"article","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18 used PET with 11C-acetate (marker for tissue oxidative capacity, which increases during BAT activity) and 18FTHA (a fatty acid tracer) in healthy males exposed to 3-hours of 18°C cold and reported an insignificant utilization of plasma FFA despite a rapid increase in BAT radiodensity, as detected by CT (a surrogate measure of TAG content in a tissue). The authors concluded that BAT prefers intracellular stores of FFAs over exogenous sources during acute bouts of mild coldADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISSN":"1558-8238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"note":"NULL","title":"Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans","type":"article","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18. These findings have been repeated in subsequent work by this same group, further supporting the notion that intracellular TAGs are the predominant substrate for BAT NST in humansADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2013-3901","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"19457197","PMID":"24423363","abstract":"Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild-cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes (T2D), which may have important pathological and therapeutic implications. Although, many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: To determine whether four weeks of daily cold exposure could increase both the volume of metabolically active brown adipose tissue (BAT) and its oxidative capacity. Design: Six non-acclimated men were exposed to 10°C, two hours daily for four weeks (5 days/week), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with (11)C-acetate and (18)F-fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake and volume prior to and following four weeks of cold acclimation were examined under controlled acute cold exposure conditions. Results: The four-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66±30 to 95±28 mL, P<0.05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725±0.300 to 1.591±0.326 mL·sec(-1), P<0.05). Shivering intensity was not significantly different pre- compared to post-acclimation (2.1±0.7 vs 2.0±0.5 %MVC, respectively). Fractional glucose uptake in BAT increased post-acclimation (from 0.035±0.014 to 0.048±0.012 min(-1)) while net glucose uptake trended towards an increase as well (from 163±60 to 209±50 nmol·g(-1)·min(-1)). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT, but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014"]]},"page":"438-446","title":"Increased Brown Adipose Tissue Oxidative Capacity in Cold-Acclimated Humans","type":"article-journal","volume":"99"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-3","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"^11,19,20","plainTextFormattedCitation":"11,19,20","previouslyFormattedCitation":"^11,19,20"},"properties":{"noteIndex":0},"schema":""}11,19,20.In recent studies using animal models, the role of stored FFAs during BAT activity has been further clarified. In addition to serving as the substrate for beta oxidation, Fedorenko et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cell.2012.09.010.Mechanism","author":[{"dropping-particle":"","family":"Fedorenko","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Lishko","given":"Polina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirichok","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"400-413","title":"Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria","type":"article-journal","volume":"151"},"uris":[""]}],"mendeley":{"formattedCitation":"²¹","plainTextFormattedCitation":"21","previouslyFormattedCitation":"²¹"},"properties":{"noteIndex":0},"schema":""}21 showed that FFAs are essential for relieving UCP1 from the potent inhibition of purine nucleotides, such as GDPADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cell.2012.09.010.Mechanism","author":[{"dropping-particle":"","family":"Fedorenko","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Lishko","given":"Polina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirichok","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"400-413","title":"Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria","type":"article-journal","volume":"151"},"uris":[""]}],"mendeley":{"formattedCitation":"²¹","plainTextFormattedCitation":"21","previouslyFormattedCitation":"²¹"},"properties":{"noteIndex":0},"schema":""}21,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.biochi.2016.10.012","ISSN":"03009084","author":[{"dropping-particle":"","family":"Klingenberg","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Biochimie","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"1-9","publisher":"Elsevier B.V","title":"UCP1- a Sophisticated Energy Valve","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"²²","plainTextFormattedCitation":"22","previouslyFormattedCitation":"²²"},"properties":{"noteIndex":0},"schema":""}22. Expectedly, these effects are augmented by cold exposure, as Xian Yu et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Yu","given":"Xing Xian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewin","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forrest","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adams","given":"Sean H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The FASEB Journal","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2002"]]},"page":"155-168","title":"Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"²³","plainTextFormattedCitation":"23","previouslyFormattedCitation":"²³"},"properties":{"noteIndex":0},"schema":""}23 reported a coordinated up regulation of FFA synthesis (i.e. genes for fatty acid synthase (FAS)) and fuel combustion in the cold-activated iBAT of mice. Therefore, it is currently understood and accepted that NST is reliant on FFA uptake, synthesis, and combustion. GlucoseThe discovery that BAT was present in appreciable amounts in adult humans was based on glucose uptake during PET/CT scanningADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0084-3741(10)79546-9","ISBN":"0028-4793","ISSN":"00843741","PMID":"19357405","abstract":"Studies in animals indicate that brown adipose tissue is important in the regulation of body weight, and it is possible that individual variation in adaptive thermogenesis can be attributed to variations in the amount or activity of brown adipose tissue. Until recently, the presence of brown adipose tissue was thought to be relevant only in small mammals and infants, with negligible physiologic relevance in adult humans. We performed a systematic examination of the presence, distribution, and activity of brown adipose tissue in lean and obese men during exposure to cold temperature. Brown-adipose-tissue activity was studied in relation to body composition and energy metabolism.","author":[{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vanhommerig","given":"Joost W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smulders","given":"N.M. Nanda M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drossaerts","given":"Jamie M a F L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kemerink","given":"Gerrit J G.J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bouvy","given":"N.D. Nicole D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schra","given":"","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teule","given":"G. J. Jaap","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teule","given":"G. J. Jaap","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The New England Journal of Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2009"]]},"page":"1500-1508","title":"Cold-Activated Brown Adipose Tissue in Healthy Men","type":"article-journal","volume":"360"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁴","plainTextFormattedCitation":"24","previouslyFormattedCitation":"²⁴"},"properties":{"noteIndex":0},"schema":""}24. At that point, glucose was presumed to be the primary fuel for NST in humans – however, in light of recent investigations (see “Lipids” section above), including the dissociation between glucose uptake and thermogenesis in UCP1-deficient miceADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.116.186460","ISBN":"4934197133","ISSN":"0161-5505","PMID":"28082439","abstract":"(18)F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain whether BAT (18)F-FDG uptake reliably tracks UCP1-mediated heat production. METHODS UCP1 knockout (UCP1 KO) and wild-type mice received the selective β3 adrenergic receptor agonist CL 316, 243 (1mg/kg) and underwent metabolic cage, infrared thermal imaging and (18)F-FDG PET/magnetic resonance imaging (MRI) experiments. Primary brown adipocytes were additionally examined for their bioenergetics as well as their uptake of 2-deoxy-3H-glucose. RESULTS In response to CL 316, 243 treatments, oxygen consumption and BAT thermogenesis were diminished in UCP1 KO mice but BAT (18)F-FDG uptake was fully retained. UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-3H-glucose uptake rates were largely unaffected. CONCLUSION Increased BAT (18)F-FDG uptake can occur independently of UCP1 function.","author":[{"dropping-particle":"","family":"Hankir","given":"Mohammed K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kranz","given":"Mathias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keipert","given":"Susanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"Juliane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreasen","given":"Sille G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kern","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patt","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kl?ting","given":"Nora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heiker","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hesse","given":"Swen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brust","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jastroch","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fenske","given":"Wiebke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"jnumed.116.186460","title":"Dissociation between brown adipose tissue 18 F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁵","plainTextFormattedCitation":"25","previouslyFormattedCitation":"²⁵"},"properties":{"noteIndex":0},"schema":""}25 and insulin-stimulated humansADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2011.06.012","author":[{"dropping-particle":"","family":"Orava","given":"Janne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lidell","given":"Martin E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oikonen","given":"Vesa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noponen","given":"Tommi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viljanen","given":"Tapio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scheinin","given":"Mika","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"page":"272-279","title":"Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁶","plainTextFormattedCitation":"26","previouslyFormattedCitation":"²⁶"},"properties":{"noteIndex":0},"schema":""}26, this notion has been questioned. Nevertheless, the involvement of glucose in BAT activity cannot be discounted entirely.As reviewed by Festuccia et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00084","ISBN":"1664-2392 (Electronic)\\r1664-2392 (Linking)","ISSN":"1664-2392","PMID":"22654830","abstract":"Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.","author":[{"dropping-particle":"","family":"Festuccia","given":"William T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanchard","given":"Pierre-Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshaies","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"December","issued":{"date-parts":[["2011"]]},"page":"1-6","title":"Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ.","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1, glucose has multiple fates once internalized by an active BAT cell. First, it can be oxidized in parallel with FFAs to fuel uncoupled respiration, though to a lesser extentADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-018-27875-3","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Held","given":"Ntsiki M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuipers","given":"Eline N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Weeghel","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Klinken","given":"Jan Bert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simone","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lombès","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wanders","given":"Ronald J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaz","given":"Frédéric M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verhoeven","given":"Arthur J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boon","given":"Mari?tte R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Houtkooper","given":"Riekelt H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"9562","issued":{"date-parts":[["2018"]]},"page":"1-12","title":"Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁷","plainTextFormattedCitation":"27","previouslyFormattedCitation":"²⁷"},"properties":{"noteIndex":0},"schema":""}27. Glucose can also be phosphorylated to glycerol-3-phosphate (G3P), which is the backbone for FFA esterification and subsequent de novo TAG synthesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00084","ISBN":"1664-2392 (Electronic)\\r1664-2392 (Linking)","ISSN":"1664-2392","PMID":"22654830","abstract":"Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.","author":[{"dropping-particle":"","family":"Festuccia","given":"William T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanchard","given":"Pierre-Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshaies","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"December","issued":{"date-parts":[["2011"]]},"page":"1-6","title":"Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ.","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1. These de novo FFA are rapidly compartmentalized into a distinct pool of TAG that are almost instantaneously oxidizedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.116.186460","ISBN":"4934197133","ISSN":"0161-5505","PMID":"28082439","abstract":"(18)F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain whether BAT (18)F-FDG uptake reliably tracks UCP1-mediated heat production. METHODS UCP1 knockout (UCP1 KO) and wild-type mice received the selective β3 adrenergic receptor agonist CL 316, 243 (1mg/kg) and underwent metabolic cage, infrared thermal imaging and (18)F-FDG PET/magnetic resonance imaging (MRI) experiments. Primary brown adipocytes were additionally examined for their bioenergetics as well as their uptake of 2-deoxy-3H-glucose. RESULTS In response to CL 316, 243 treatments, oxygen consumption and BAT thermogenesis were diminished in UCP1 KO mice but BAT (18)F-FDG uptake was fully retained. UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-3H-glucose uptake rates were largely unaffected. CONCLUSION Increased BAT (18)F-FDG uptake can occur independently of UCP1 function.","author":[{"dropping-particle":"","family":"Hankir","given":"Mohammed K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kranz","given":"Mathias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keipert","given":"Susanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"Juliane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreasen","given":"Sille G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kern","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patt","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kl?ting","given":"Nora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heiker","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hesse","given":"Swen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brust","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jastroch","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fenske","given":"Wiebke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"jnumed.116.186460","title":"Dissociation between brown adipose tissue 18 F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"15-30","title":"Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes","type":"article-journal","volume":"58"},"uris":[""]}],"mendeley":{"formattedCitation":"^25,28","plainTextFormattedCitation":"25,28","previouslyFormattedCitation":"^25,28"},"properties":{"noteIndex":0},"schema":""}25,28. Glucose is also presumed to play a complementary role in this process, as it can be catabolized (from its monomeric state or as glycogen) to generate energy for further TAG synthesis or other cell processes such as lipolysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00084","ISBN":"1664-2392 (Electronic)\\r1664-2392 (Linking)","ISSN":"1664-2392","PMID":"22654830","abstract":"Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.","author":[{"dropping-particle":"","family":"Festuccia","given":"William T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanchard","given":"Pierre-Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshaies","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"December","issued":{"date-parts":[["2011"]]},"page":"1-6","title":"Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ.","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1. In the context of BAT thermogenesis, these functions are indispensable – TAG stores need to be replenished once depleted and the uncoupling of ATP synthesis from oxidative phosphorylation will create a state of heightened energy demand. Considered together, the above notions feed back on the idea that FFAs are the primary source of fuel for BAT.Factors associated with brown adipose tissue presence and activityTo date, numerous studies in both adults and children have sought to identify the factors, both modifiable and non-modifiable, which might help to explain the observed variations in BAT prevalence and activity. Among those investigated, age, sex, body composition, and temperature have emerged as plausible predictors.AgeThe inverse relationship between BAT (i.e. presence and activity) and age is well describedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0810780","ISBN":"1533-4406 (Electronic)\\n0028-4793 (Linking)","ISSN":"0028-4793","PMID":"19357406","abstract":"Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehman","given":"Sanaz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Williams","given":"Gethin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodman","given":"Dean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldfine","given":"Allison B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuo","given":"Frank C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Edwin L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doria","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C. Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2009","4"]]},"page":"1509-1517","title":"Identification and Importance of Brown Adipose Tissue in Adult Humans","type":"article-journal","volume":"360"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1038/oby.2011.125","ISBN":"1930-7381 (Print)\\r1930-7381 (Linking)","ISSN":"1930-7381","PMID":"21566561","abstract":"Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 °C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.","author":[{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aita","given":"Sayuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity (Silver Spring, Md.)","id":"ITEM-4","issue":"9","issued":{"date-parts":[["2011"]]},"page":"1755-60","publisher":"Nature Publishing Group","title":"Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.","type":"article-journal","volume":"19"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.2967/jnumed.115.165829","ISSN":"1535-5667","PMID":"26609175","abstract":"Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold.\\n\\nMETHODS: This was a prospective observational study. We included 10 young obese, 11 old lean and 14 young lean healthy males. All subjects underwent a (18)F-Fluorodeoxyglucose ((18)F-FDG) PET-CT and a (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT-CT after an overnight fast and two hours of cold exposure. Metabolic BAT activity was expressed as volume and as maximal standardised uptake value (SUVmax) of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG).\\n\\nRESULTS: SUVmax, BAT volume and SQUVmax were significantly different between young and old (SUVmax 7.9[4.2-17.3] vs. 2.9[0.0-4.0], volume 124.8[10.9-338.8] vs 3.4 [0.0-10.9] and SQUVmax 2.7[1.9-4.7] vs 0.0[0.0-2.2] all p<0.01) but not between lean and obese (SUVmax 7.9[4.2-17.3] vs 4.0[0.0-13.5] P = 0.69; volume 124.8[10.9-338.8] vs 11.8 [0.0-190.2] P = 0.64 and SQUVmax 2.7[1.9-4.7]vs 1.7[0-3.5] P = 0.69). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT positive subjects (ρ=0.82, p<0.01).\\n\\nCONCLUSION: We conclude that both sympathetic drive and BAT activity are lower in older but not in obese males.","author":[{"dropping-particle":"","family":"Bahler","given":"Lonneke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verberne","given":"Hein J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Admiraal","given":"Wanda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stok","given":"Wim J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soeters","given":"Maarten R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoekstra","given":"Joost B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holleman","given":"Frits","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nuclear Medicine","id":"ITEM-5","issue":"3","issued":{"date-parts":[["2016"]]},"page":"1-27","title":"Differences in Sympathetic Nervous Stimulation of Brown Adipose tissue between the young and old and the lean and obese.","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"^29–33","plainTextFormattedCitation":"29–33","previouslyFormattedCitation":"^29–33"},"properties":{"noteIndex":0},"schema":""}29–33. As previously mentioned, there is a significantly higher prevalence of detectible BAT in pediatric compared to adult populationsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. Among the latter group, Yoneshiro et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/oby.2011.125","ISBN":"1930-7381 (Print)\\r1930-7381 (Linking)","ISSN":"1930-7381","PMID":"21566561","abstract":"Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 °C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.","author":[{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aita","given":"Sayuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity (Silver Spring, Md.)","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2011"]]},"page":"1755-60","publisher":"Nature Publishing Group","title":"Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"³²","plainTextFormattedCitation":"32","previouslyFormattedCitation":"³²"},"properties":{"noteIndex":0},"schema":""}32 found an age-related decrease in the prevalence of cold-activated BAT, wherein 50% of participants in their 20s versus less than 10% of those above the age of 50 had detectible 18F-FDG uptake. Similarly, Bahler et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.115.165829","ISSN":"1535-5667","PMID":"26609175","abstract":"Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold.\\n\\nMETHODS: This was a prospective observational study. We included 10 young obese, 11 old lean and 14 young lean healthy males. All subjects underwent a (18)F-Fluorodeoxyglucose ((18)F-FDG) PET-CT and a (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT-CT after an overnight fast and two hours of cold exposure. Metabolic BAT activity was expressed as volume and as maximal standardised uptake value (SUVmax) of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG).\\n\\nRESULTS: SUVmax, BAT volume and SQUVmax were significantly different between young and old (SUVmax 7.9[4.2-17.3] vs. 2.9[0.0-4.0], volume 124.8[10.9-338.8] vs 3.4 [0.0-10.9] and SQUVmax 2.7[1.9-4.7] vs 0.0[0.0-2.2] all p<0.01) but not between lean and obese (SUVmax 7.9[4.2-17.3] vs 4.0[0.0-13.5] P = 0.69; volume 124.8[10.9-338.8] vs 11.8 [0.0-190.2] P = 0.64 and SQUVmax 2.7[1.9-4.7]vs 1.7[0-3.5] P = 0.69). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT positive subjects (ρ=0.82, p<0.01).\\n\\nCONCLUSION: We conclude that both sympathetic drive and BAT activity are lower in older but not in obese males.","author":[{"dropping-particle":"","family":"Bahler","given":"Lonneke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verberne","given":"Hein J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Admiraal","given":"Wanda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stok","given":"Wim J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soeters","given":"Maarten R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoekstra","given":"Joost B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holleman","given":"Frits","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nuclear Medicine","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2016"]]},"page":"1-27","title":"Differences in Sympathetic Nervous Stimulation of Brown Adipose tissue between the young and old and the lean and obese.","type":"article-journal","volume":"57"},"uris":[""]}],"mendeley":{"formattedCitation":"³³","plainTextFormattedCitation":"33","previouslyFormattedCitation":"³³"},"properties":{"noteIndex":0},"schema":""}33 observed a reduced sympathetic drive to BAT in old (mean of 54 years) compared to young (mean of 25.5 years) men following a 2-hour cold exposure. However, much of the data concerning this relationship was derived from retrospective analyses and should therefore be interpreted with cautionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/pr.2012.141","ISBN":"1530-0447","ISSN":"1530-0447","PMID":"23090604","abstract":"Brown adipose tissue (BAT) was thought to disappear after infancy. Recent findings of BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggest that BAT is more prevalent in children than in adults and that its activation during adolescence is associated with significantly lower gains in weight and adiposity. Data also show that pediatric patients with metabolically active BAT on PET/CT examinations have significantly greater muscle volume than patients without identifiable BAT. Both the activity and the amount of BAT increase during puberty. The magnitude of the increase is higher in boys as compared with girls and is closely related to gains in muscle volume. Hence, concurrent with the gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between brown adipocytes, white adipocytes, and myocytes. In this review, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children.","author":[{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric research","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"3-9","title":"Relevance of brown adipose tissue in infancy and adolescence.","type":"article-journal","volume":"73"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"³"},"properties":{"noteIndex":0},"schema":""}3.SexThere is much debate as to whether or not BAT prevalence and activity is sex-specific. In a retrospective analysis of routine clinical PET/CT scans, both Ouellet et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"³¹","plainTextFormattedCitation":"31","previouslyFormattedCitation":"³¹"},"properties":{"noteIndex":0},"schema":""}31 and Cypess et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0810780","ISBN":"1533-4406 (Electronic)\\n0028-4793 (Linking)","ISSN":"0028-4793","PMID":"19357406","abstract":"Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehman","given":"Sanaz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Williams","given":"Gethin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodman","given":"Dean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldfine","given":"Allison B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuo","given":"Frank C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Edwin L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doria","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C. Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2009","4"]]},"page":"1509-1517","title":"Identification and Importance of Brown Adipose Tissue in Adult Humans","type":"article-journal","volume":"360"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁹","plainTextFormattedCitation":"29","previouslyFormattedCitation":"²⁹"},"properties":{"noteIndex":0},"schema":""}29 concluded that the prevalence of 18F-FDG uptake in BAT was significantly greater in women than men. However, a subsequent prospective study by the latter group did not observe a significant sexual dimorphism in any measure of cold-induced BAT functionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1207911109","ISBN":"0027-8424","ISSN":"1091-6490","PMID":"22665804","abstract":"As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by (18)F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Yih-Chieh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sze","given":"Cathy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Ke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"English","given":"Jeffrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chan","given":"Onyee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holman","given":"Ashley R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2012","6"]]},"page":"10001-10005","publisher":"National Academy of Sciences","title":"Cold but not sympathomimetics activates human brown adipose tissue in vivo.","type":"article-journal","volume":"109"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁴","plainTextFormattedCitation":"34","previouslyFormattedCitation":"³⁴"},"properties":{"noteIndex":0},"schema":""}34. Given the heterogeneous nature of evidence to dateADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e., close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) imaging. Dynamic imaging provides quantitative information about glucose uptake rates, whereas static imaging reflects overall BAT glucose uptake, localization, and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET image, leading to spillover. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [18F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the “fixed volume” methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like magnetic resonance imaging or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"A. A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"M. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"W. D.","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"R103-R113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹","plainTextFormattedCitation":"9","previouslyFormattedCitation":"⁹"},"properties":{"noteIndex":0},"schema":""}9, no definitive conclusions can be made. What is clear is that hormonal changes, particularly during a female’s menstrual cycle, may introduce confounding effects on thermogenesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2011.09.035","ISBN":"2122633255","ISSN":"00223476","PMID":"22048045","abstract":"Objective: To characterize the changes in brown adipose tissue (BAT) occurring during puberty in boys and girls. Study design: We examined the prevalence and the volume of BAT at different stages of sexual development in 73 pediatric patients who underwent positron emission tomography (PET)/computed tomography (CT) studies. Results: Of the 73 patients studied, 43 (59%) had BAT depicted on PET/CT. The presence of BAT was detected significantly less frequently on PET/CT in prepubertal subjects (Tanner stage 1) than in pubertal subjects (Tanner stages 2-5) (15% vs 75%). BAT volume also increased during puberty, with a significantly greater magnitude of the increase in the final 2 stages of puberty (Tanner stages 4 and 5) than in earlier stages (Tanner stages 1-3) (boys: 499 ?? 246 vs 50 ?? 36, P <.0001; girls: 286 ?? 139 vs 36 ?? 29, P =.024). Changes in BAT volume were also significantly greater in boys than in girls (P =.004) and were closely related to muscle volume (r = 0.52, P <.01 for boys; r = 0.64, P <.01 for girls). Conclusion: The presence and volume of BAT increase rapidly during puberty. Metabolic and hormonal events related to the achievement of sexual maturity are likely responsible for this increase. Copyright ?? 2012 Mosby Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Michelle L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goodarzian","given":"Fariba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Mimi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wren","given":"Tishya A L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2012"]]},"page":"604-609.e1","publisher":"Mosby, Inc.","title":"Changes in brown adipose tissue in boys and girls during childhood and puberty","type":"article-journal","volume":"160"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁵","plainTextFormattedCitation":"35","previouslyFormattedCitation":"³⁵"},"properties":{"noteIndex":0},"schema":""}35 and should therefore be considered in the design of studies.Body CompositionTo date, there is an established relationship between BAT activity and indices of body composition – namely body mass index (BMI) and % total body fat – in humans. In retrospective studies, a higher uptake of 18F-FDG in the SCV of subjects with lower BMIADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0810780","ISBN":"1533-4406 (Electronic)\\n0028-4793 (Linking)","ISSN":"0028-4793","PMID":"19357406","abstract":"Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehman","given":"Sanaz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Williams","given":"Gethin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodman","given":"Dean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldfine","given":"Allison B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuo","given":"Frank C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Edwin L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doria","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C. Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2009","4"]]},"page":"1509-1517","title":"Identification and Importance of Brown Adipose Tissue in Adult Humans","type":"article-journal","volume":"360"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1152/ajpendo.00298.2010.","ISBN":"1522-1555 (Electronic)\\r0193-1849 (Linking)","ISSN":"0193-1849","PMID":"20606075","abstract":"Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.","author":[{"dropping-particle":"","family":"Lee","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenfield","given":"Jerry R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ho","given":"Ken K Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fulham","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Endocrinology and Metabolism","id":"ITEM-4","issue":"4","issued":{"date-parts":[["2010","10"]]},"page":"601-606","title":"A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans","type":"article-journal","volume":"299"},"uris":[""]}],"mendeley":{"formattedCitation":"^29–31,36","plainTextFormattedCitation":"29–31,36","previouslyFormattedCitation":"^29–31,36"},"properties":{"noteIndex":0},"schema":""}29–31,36 and less adiposity was observedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁰","plainTextFormattedCitation":"30","previouslyFormattedCitation":"³⁰"},"properties":{"noteIndex":0},"schema":""}30. Orava et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/oby.20456","author":[{"dropping-particle":"","family":"Orava","given":"Janne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noponen","given":"Tommi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viljanen","given":"Tapio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enerback","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rissanen","given":"Aila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pietilainen","given":"Kirsi H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2013"]]},"page":"2279-2287","title":"Blunted Metabolic Responses to Cold and Insulin Stimulation in Brown Adipose Tissue of Obese Humans","type":"article-journal","volume":"21"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁷","plainTextFormattedCitation":"37","previouslyFormattedCitation":"³⁷"},"properties":{"noteIndex":0},"schema":""}37 furthered these initial findings in a prospective study wherein lean subjects exhibited heightened cold-induced BAT glucose uptake and blood flow compared to their obese counterparts. Finally, Deng and colleaguesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 combined magnetic resonance imaging (MRI)-specific BAT measurements with an individualized cooling protocol (i.e. one hour at a temperature just above one’s threshold for self-reported shivering) in 15 male subjects under the age of 30. This group concluded that fat fraction (FF), a tissue-specific MRI property which will be discussed in Section 1.4.2 below, was significantly higher in obese compared to lean subjects in both thermoneutral and cold-activated states. Furthermore, FF was negatively correlated with the volume of metabolically active BAT (i.e. 18F-FDG uptake) (r=-0.55), suggesting that those with greater adiposity had a blunted BAT-specific response to coldADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38. In closing, the relationship between BAT activity and indices of body composition has arguably been the most convincing and consistent among the available evidence.Environmental FactorsAmbient room and outdoor temperatures near the time of data collection have also been shown to influence BAT-specific outcomesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00259-008-0983-y","ISSN":"16197070","PMID":"19037639","abstract":"PURPOSE: The aim of this study was to determine if warming patients prior to and during (18)F-FDG uptake by controlling the room temperature could decrease uptake by brown adipose tissue (BAT).\\n\\nMETHODS: A group of 40 children underwent (18)F-FDG PET after being kept in the injection room at a constant temperature of 24 degrees C for half an hour before and 1 hour after intravenous tracer administration. The rate of uptake by BAT in this group was compared to the uptake in a control group of 45 patients who underwent PET when the injection room temperature was 21 degrees C.\\n\\nRESULTS: Uptake by BAT occurred in 5% of studies in the temperature-controlled room compared to 31% of studies performed when the injection room temperature was 21 degrees C (p<0.002).\\n\\nCONCLUSION: Maintaining room temperature at a constant 24 degrees C, half an hour prior to and during the period of FDG uptake significantly decreases accumulation of FDG in BAT in children.","author":[{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahey","given":"Frederic H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laffin","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davis","given":"Royal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Treves","given":"S. Ted","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grant","given":"Frederick D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2009"]]},"page":"602-606","title":"Constant ambient temperature of 24°C significantly reduces FDG uptake by brown adipose tissue in children scanned during the winter","type":"article-journal","volume":"36"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00259-010-1485-2","ISBN":"1619-7089 (Electronic)\\r1619-7070 (Linking)","ISSN":"16197070","PMID":"20505932","abstract":"It has been shown that warming patients prior to and during (18)F-FDG uptake by controlling the room temperature can decrease uptake by brown adipose tissue (BAT). The aim of this study is to determine if this effect is subject to seasonal variation.","author":[{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahey","given":"Frederic H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laffin","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davis","given":"Royal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Treves","given":"S. Ted","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grant","given":"Frederick D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2010"]]},"page":"1854-1860","title":"Seasonal variation in the effect of constant ambient temperature of 24°C in reducing FDG uptake by brown adipose tissue in children","type":"article-journal","volume":"37"},"uris":[""]},{"id":"ITEM-3","itemData":{"ISSN":"01615505","author":[{"dropping-particle":"","family":"Cohade","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mourtzikos","given":"Karen A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-3","issued":{"date-parts":[["2003"]]},"page":"1267-1271","title":"“ USA-Fat ”: Prevalence Is Related to Ambient Outdoor Temperature — Evaluation with 18 F-FDG PET/CT","type":"article-journal","volume":"44"},"uris":[""]}],"mendeley":{"formattedCitation":"^39–41","plainTextFormattedCitation":"39–41","previouslyFormattedCitation":"^39–41"},"properties":{"noteIndex":0},"schema":""}39–41. In particular, Zukotynski et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00259-008-0983-y","ISSN":"16197070","PMID":"19037639","abstract":"PURPOSE: The aim of this study was to determine if warming patients prior to and during (18)F-FDG uptake by controlling the room temperature could decrease uptake by brown adipose tissue (BAT).\\n\\nMETHODS: A group of 40 children underwent (18)F-FDG PET after being kept in the injection room at a constant temperature of 24 degrees C for half an hour before and 1 hour after intravenous tracer administration. The rate of uptake by BAT in this group was compared to the uptake in a control group of 45 patients who underwent PET when the injection room temperature was 21 degrees C.\\n\\nRESULTS: Uptake by BAT occurred in 5% of studies in the temperature-controlled room compared to 31% of studies performed when the injection room temperature was 21 degrees C (p<0.002).\\n\\nCONCLUSION: Maintaining room temperature at a constant 24 degrees C, half an hour prior to and during the period of FDG uptake significantly decreases accumulation of FDG in BAT in children.","author":[{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fahey","given":"Frederic H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laffin","given":"Stephen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davis","given":"Royal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Treves","given":"S. Ted","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grant","given":"Frederick D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2009"]]},"page":"602-606","title":"Constant ambient temperature of 24°C significantly reduces FDG uptake by brown adipose tissue in children scanned during the winter","type":"article-journal","volume":"36"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁹","plainTextFormattedCitation":"39","previouslyFormattedCitation":"³⁹"},"properties":{"noteIndex":0},"schema":""}39 found that maintaining a constant room temperature of 24°C versus 21°C during 18F-FDG administration and PET scanning significantly decreased the intensity of radiotracer uptake by SCV BAT. Furthermore, Saito et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁰","plainTextFormattedCitation":"30","previouslyFormattedCitation":"³⁰"},"properties":{"noteIndex":0},"schema":""}30 identified a seasonal variation in the presence of detectible BAT activity between individuals, wherein those enrolled in the winter months exhibited heightened cold-induced 18F-FDG uptake compared to those whose measurements were obtained in the summer. Due to these initial findings, methodologies have since incorporated an acclimatization phase (i.e. a period of time spent in a warm/thermoneutral room before cold exposure and/or BAT measurements) which is thought to mitigate the effects of acute exposure to colder ambient temperatures prior to BAT measurementsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42.BAT imagingThere is currently a diverse array of imaging modalities based on the properties of BAT that undergo a measurable change during a state of activation, and these have all been instrumental in establishing the aforementioned predictors. A number of recent reviews have discussed each of these technologies in detailADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/JP274255","author":[{"dropping-particle":"","family":"Chondronikola","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beeman","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Physiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"363-378","title":"Non-Invasive Methods for the Assessment of Brown Adipose Tissue in Humans","type":"article-journal","volume":"593"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.ymeth.2017.05.001","ISSN":"1046-2023","author":[{"dropping-particle":"","family":"Paulus","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bauwens","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Marken","given":"Wouter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bauwens","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Methods","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Elsevier Inc.","title":"Brown adipose tissue and lipid metabolism imaging","type":"article-journal"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.tem.2013.12.004","ISSN":"1043-2760","author":[{"dropping-particle":"","family":"Townsend","given":"Kristy L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-hua","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Trends in Endocrinology & Metabolism","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2014"]]},"page":"168-177","publisher":"Elsevier Ltd","title":"Brown fat fuel utilization and thermogenesis","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"^43–45","plainTextFormattedCitation":"43–45","previouslyFormattedCitation":"^43–45"},"properties":{"noteIndex":0},"schema":""}43–45 – however the most established in terms of accuracy and overall robustness are 18F-FDG PET/CT and MRI FF.18F-FDG PET/CTAs evidenced by the numerous aforementioned reports using PET to detect 18F-FDG uptake by metabolically active BAT, it is currently the reference standardADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00247-010-1925-y","ISBN":"1432-1998 (Electronic)\\n0301-0449 (Linking)","ISSN":"03010449","PMID":"21161205","abstract":"Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET.","author":[{"dropping-particle":"","family":"Hong","given":"Terence S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shammas","given":"Amer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Charron","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2011"]]},"page":"759-768","title":"Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging","type":"article-journal","volume":"41"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}4. Static and dynamic approaches to this modality have been fundamental in triggering and advancing our knowledge of the identification, location, and nature of BAT in humansADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00298.2010.","ISBN":"1522-1555 (Electronic)\\r0193-1849 (Linking)","ISSN":"0193-1849","PMID":"20606075","abstract":"Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.","author":[{"dropping-particle":"","family":"Lee","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenfield","given":"Jerry R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ho","given":"Ken K Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fulham","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Endocrinology and Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010","10"]]},"page":"601-606","title":"A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans","type":"article-journal","volume":"299"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁶","plainTextFormattedCitation":"36","previouslyFormattedCitation":"³⁶"},"properties":{"noteIndex":0},"schema":""}36. Furthermore, harmonizing 18F-FDG PET with CT radio-density (in Hounsfield units; HUs) offers anatomical localization of radiotracer uptake and a surrogate measurement of intracellular TAG consumption during BAT NSTADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.109.068775","ISBN":"1535-5667 (Electronic) 0161-5505 (Linking)","ISSN":"0161-5505","PMID":"20124047","abstract":"Brown adipose tissue (BAT) densities assessed as CT Hounsfield units (HUs) were evaluated in a rodent model and in patients to determine whether HUs changed in relation to BAT activity. METHODS: Serial (18)F-FDG PET/CT was performed on rats under both room temperature control conditions and after 4 h of cold-stimulation, which is known to activate BAT. The maximum standardized uptake values and CT HUs of BAT were measured, and tissues were examined in the laboratory. Image records from cancer patients who underwent PET/CT were reviewed, and 23 patients were identified who displayed both high and low (18)F-FDG uptake into BAT on serial (18)F-FDG PET/CT scans. The maximum standardized uptake values and CT HUs of BAT were compared in these scans. RESULTS: The mean (+/-SD) CT HUs of cold-activated BAT (-12.4 +/- 22.4) were significantly higher than those (-27.9 +/- 9.6) of the controls in the rat model. The CT HUs of BAT (-71.6 +/- 18.0) in the patients with high (18)F-FDG uptake were significantly higher than those (-104.4 +/- 16.8) of the patients with low (18)F-FDG uptake . A decrease in relative lipid content is seen in activated BAT in rats on histology. CONCLUSION: The CT HUs of BAT increased in activated conditions in both animals and patients, likely because of lipid consumption by activated BAT.","author":[{"dropping-particle":"","family":"Baba","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacene","given":"Heather A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Engles","given":"James M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honda","given":"Hiroshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nuclear Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2010","2"]]},"page":"246-251","publisher":"Society of Nuclear Medicine","title":"CT Hounsfield Units of Brown Adipose Tissue Increase with Activation: Preclinical and Clinical Studies","type":"article-journal","volume":"51"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2217/clp.15.14","ISSN":"17584302 17584299","abstract":"The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P DP","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Lipidology","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2015"]]},"page":"259-280","title":"A critical appraisal of brown adipose tissue metabolism in humans","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"^46,47","plainTextFormattedCitation":"46,47","previouslyFormattedCitation":"^46,47"},"properties":{"noteIndex":0},"schema":""}46,47. However there are a number of limitations associated with this modality which include: 1) Injection of a radioactive analogue, such as 18F-FDG, may be harmful to healthy and young cohorts and thus strict radioactivity exposure guidelines must be observedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2016.07.014","ISSN":"19327420","abstract":"Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked.","author":[{"dropping-particle":"","family":"Chen","given":"Kong Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laughlin","given":"Maren R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haft","given":"Carol R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bredella","given":"Miriam A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enerb?ck","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinahan","given":"Paul E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lichtenbelt","given":"Wouter Van Marken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Frank I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sunderland","given":"John J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2016"]]},"page":"210-222","title":"Perspective Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁸","plainTextFormattedCitation":"48","previouslyFormattedCitation":"⁴⁸"},"properties":{"noteIndex":0},"schema":""}48; 2) 18F-FDG considers only glucose utilization by BAT, which may lead to an underestimation of tissue mass and overall activityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"103-113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁹","plainTextFormattedCitation":"49","previouslyFormattedCitation":"⁴⁹"},"properties":{"noteIndex":0},"schema":""}49; 3) In the absence of a sympathetic stimulus, such as cold exposure, PET/CT exhibits poor reproducibilityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00298.2010.","ISBN":"1522-1555 (Electronic)\\r0193-1849 (Linking)","ISSN":"0193-1849","PMID":"20606075","abstract":"Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.","author":[{"dropping-particle":"","family":"Lee","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenfield","given":"Jerry R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ho","given":"Ken K Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fulham","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Endocrinology and Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2010","10"]]},"page":"601-606","title":"A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans","type":"article-journal","volume":"299"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁶","plainTextFormattedCitation":"36","previouslyFormattedCitation":"³⁶"},"properties":{"noteIndex":0},"schema":""}36, and 4) The use of 18F-FDG assumes that glucose uptake reflects BAT activity; however it has been recently demonstrated that fatty acids from intracellular TAG lipolysis are the primary substrates for BAT-derived thermogenesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00247-010-1925-y","ISBN":"1432-1998 (Electronic)\\n0301-0449 (Linking)","ISSN":"03010449","PMID":"21161205","abstract":"Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET.","author":[{"dropping-particle":"","family":"Hong","given":"Terence S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shammas","given":"Amer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Charron","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2011"]]},"page":"759-768","title":"Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging","type":"article-journal","volume":"41"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2016.12.005","ISSN":"19327420","PMID":"28089568","abstract":"Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C. Andre C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C. Andre C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2017"]]},"page":"438-447","title":"Inhibition of Intracellular Triglyceride Lipolysis Suppresses Cold-Induced Brown Adipose Tissue Metabolism and Increases Shivering in Humans","type":"article-journal","volume":"25"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1096/fj.14-266247","author":[{"dropping-particle":"","family":"Labb?","given":"Sebastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Caron","given":"Alexandre","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bakan","given":"Inan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laplante","given":"Mathieu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"Andre C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lecomte","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The FASEB Journal","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2015"]]},"page":"2046-2058","title":"In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"^4,50,51","plainTextFormattedCitation":"4,50,51","previouslyFormattedCitation":"^4,50,51"},"properties":{"noteIndex":0},"schema":""}4,50,51.Given these evident shortcomings that ultimately preclude the widespread use of PET/CT outside of the diagnostic setting, alternative modalities for BAT detection and quantification must be realized.MRI Fat FractionChemical-shift MRI and its many sensitive and flexible contrast mechanisms can safely and non-invasively identify SCV BAT morphology and activityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1467-789X.2010.00824.x","ISBN":"1467-789X","ISSN":"14677881","PMID":"21348916","abstract":"As the prevalence of obesity continues to rise, rapid and accurate tools for assessing abdominal body and organ fat quantity and distribution are critically needed to assist researchers investigating therapeutic and preventive measures against obesity and its comorbidities. Magnetic resonance imaging (MRI) is the most promising modality to address such need. It is non-invasive, utilizes no ionizing radiation, provides unmatched 3-D visualization, is repeatable, and is applicable to subject cohorts of all ages. This article is aimed to provide the reader with an overview of current and state-of-the-art techniques in MRI and associated image analysis methods for fat quantification. The principles underlying traditional approaches such as T1-weighted imaging and magnetic resonance spectroscopy as well as more modern chemical-shift imaging techniques are discussed and compared. The benefits of contiguous 3-D acquisitions over 2-D multislice approaches are highlighted. Typical post-processing procedures for extracting adipose tissue depot volumes and percent organ fat content from abdominal MRI data sets are explained. Furthermore, the advantages and disadvantages of each MRI approach with respect to imaging parameters, spatial resolution, subject motion, scan time and appropriate fat quantitative endpoints are also provided. Practical considerations in implementing these methods are also presented.","author":[{"dropping-particle":"","family":"Hu","given":"H. H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"K. S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goran","given":"M. I.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity Reviews","id":"ITEM-1","issue":"501","issued":{"date-parts":[["2011"]]},"note":"NULL","page":"504-515","title":"Assessment of abdominal adipose tissue and organ fat content by magnetic resonance imaging","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵²","plainTextFormattedCitation":"52","previouslyFormattedCitation":"⁵²"},"properties":{"noteIndex":0},"schema":""}52. Namely, the Iterative Decomposition with Echo-Asymmetry and Least squares estimation (IDEAL) is an accurate and reproducible fat-water separation technique built within certain General Electric scanners that computes the proton density fat fraction (PDFF) of a region of interest (ROI) while accounting for various confounding variablesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.22162.","ISBN":"8585348585","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"DL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"KS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goran","given":"MI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy","given":"TR","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2010"]]},"page":"1195-1202","title":"Identification of Brown Adipose Tissue in Mice with Fat-Water IDEAL-MRI","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵³","plainTextFormattedCitation":"53","previouslyFormattedCitation":"⁵³"},"properties":{"noteIndex":0},"schema":""}53. In short, PDFF, or FF, is reflective of the relative amounts of fat and water within a given ROI, and is therefore capable of distinguishing adipose from non-adipose tissuesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.115.160770","ISSN":"0161-5505","PMID":"26272809","abstract":"UNLABELLED: The purpose of the study was to evaluate signal-fat-fraction (SFF) analysis based on a 2-point-Dixon water-fat separation method in whole-body simultaneous PET/MR imaging for identifying brown adipose tissue (BAT) and discriminating it from white adipose tissue (WAT) using cross-validation via PET.\\n\\nMETHODS: This retrospective, internal review board-approved study evaluated 66 PET/MR imaging examinations of 33 pediatric patients (mean age, 14.7 y; range, 7.4-21.4 y). Eleven elderly patients were evaluated as controls (mean age, 79.9 y; range, 76.3-88.6 y). Pediatric patients were divided into 2 groups: with and without metabolically active supraclavicular BAT. The standard of reference for the presence of BAT was at least 1 PET examination showing (18)F-FDG uptake. PET/MR imaging included a 2-point Dixon water-fat separation method. Signal intensities in regions of interest on fat and water images and mean standardized uptake values (SUVmean) were determined bilaterally in supraclavicular and gluteal fat depots. SFF was calculated from the ratio of fat signal over summed water and fat signal. Statistical analysis was conducted using the Student t test and correlation analysis.\\n\\nRESULTS: SFF was significantly lower (P < 0.0001) in supraclavicular BAT than gluteal WAT in all pediatric subjects. Supraclavicular SFF was significantly higher in the control than in the pediatric group (P < 0.0001). In PET-positive patients with multiple examinations, SFF stayed stable whereas SUVmean fluctuated (median intraindividual change, 5% vs. 91%). No significant correlation between SUVmean and SFF could be observed for BAT.\\n\\nCONCLUSION: The results demonstrate that MR imaging-SFF analysis is a reproducible imaging modality for the detection of human BAT and discrimination from WAT. SFF values of BAT are independent from its metabolic activity, making SFF a more reliable parameter for BAT than the commonly used PET signal. However, with the intent to investigate both the composition of BAT and its activation status, hybrid PET/MR imaging might provide supplemental information.","author":[{"dropping-particle":"","family":"Franz","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karampinos","given":"D. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rummeny","given":"E. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Souvatzoglou","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beer","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nekolla","given":"S. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwaiger","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eiber","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2015"]]},"page":"1742-1747","title":"Discrimination Between Brown and White Adipose Tissue Using a 2-Point Dixon Water-Fat Separation Method in Simultaneous PET/MRI","type":"article-journal","volume":"56"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁴","plainTextFormattedCitation":"54","previouslyFormattedCitation":"⁵⁴"},"properties":{"noteIndex":0},"schema":""}54. It is also presumed that the multilocular nature of BAT would translate to consistently lower basal FF values compared to WAT – however the idea that morphologically distinct adipose tissue depots have unique FF signatures is debatableADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-2","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/nbm.3444","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"26620447","abstract":"The supraclavicular fat depot is known for brown adipose tissue presence. To unravel adipose tissue physiology and metabolism, high quality and reproducible imaging is required. In this study we quantified the reliability and agreement of MRI fat fraction measurements in supraclavicular and subcutaneous adipose tissue of 25 adult patients with clinically manifest cardiovascular disease. MRI fat fraction measurements were made under ambient temperature conditions using a vendor supplied mDixon chemical-shift water-fat multi-echo pulse sequence at 1.5 T field strength. Supraclavicular fat fraction reliability (intraclass correlation coefficientagreement , ICCagreement ) was 0.97 for test-retest, 0.95 for intra-observer and 0.56 for inter-observer measurements, which increased to 0.88 when ICCconsistency was estimated. Supraclavicular fat fraction agreement displayed mean differences of 0.5% (limit of agreement (LoA) -1.7 to 2.6) for test-retest, -0.5% (LoA -2.9 to 2.0) for intra-observer and 5.6% (LoA 0.4 to 10.8) for inter-observer measurements. Median fat fraction in supraclavicular adipose tissue was 82.5% (interquartile range (IQR) 78.6-84.0) and 89.7% (IQR 87.2-91.5) in subcutaneous adipose tissue (p < 0.0001). In conclusion, water-fat MRI has good reliability and agreement to measure adipose tissue fat fraction in patients with manifest cardiovascular disease. These findings enable research on determinants of fat fraction and enable longitudinal monitoring of fat fraction within adipose tissue depots. Interestingly, even in adult patients with manifest cardiovascular disease, supraclavicular adipose tissue has a lower fat fraction compared with subcutaneous adipose tissue, suggestive of distinct morphologic characteristics, such as brown adipose tissue. Copyright (c) 2015 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikendal","given":"Anouk L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR in Biomedicine","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"48-56","title":"Reliability and agreement of adipose tissue fat fraction measurements with water-fat MRI in patients with manifest cardiovascular disease","type":"article-journal","volume":"29"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-4","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.mri.2018.04.013","ISSN":"0730725X","author":[{"dropping-particle":"","family":"Jones","given":"Terence A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wayte","given":"Sarah C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reddy","given":"Narendra L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adesanya","given":"Oludolapo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitriadis","given":"George K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barber","given":"Thomas M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutchinson","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Imaging","id":"ITEM-5","issue":"3","issued":{"date-parts":[["2018"]]},"page":"61-68","publisher":"Elsevier","title":"Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps","type":"article-journal","volume":"51"},"uris":[""]}],"mendeley":{"formattedCitation":"^55–59","plainTextFormattedCitation":"55–59","previouslyFormattedCitation":"^55–59"},"properties":{"noteIndex":0},"schema":""}55–59. With regards to the utility of FF in between-subject analyses, Deng and colleaguesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 used a receiver operating characteristic curve to demonstrate 100% sensitivity and specificity for the use of SCV BAT FF in differentiating between lean and obese subjects under non cold-stimulated conditions (i.e. higher SCV BAT FF with greater whole-body adiposity; FF cutoff =83% in their population of 6 normal and 9 overweight/obese young males). Furthermore, BAT is densely innervated by the SNS and upon activation, intracellular TAGs are rapidly mobilized and consumed, which MRI captures as a decrease in FFADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00033","ISBN":"1664-2392","ISSN":"16642392","PMID":"22649372","abstract":"Fusion positron emission and computed tomography (PET/CT) remains the gold-standard imaging modality to non-invasively study metabolically active brown adipose tissue (BAT). It has been widely applied to studies in adult cohorts. In contrast, the number of BAT studies in children has been few. This is largely limited by the elevated risk of ionizing radiation and radionuclide tracer usage by PET/CT and the ethical restriction of performing such exams on healthy children. However, metabolically active BAT has a significantly higher prevalence in pediatric patients, according to recent literature. Young cohorts thus represent an ideal population to examine the potential relationships of BAT to muscle development, puberty, disease state, and the accumulation of white adipose tissue. In turn, magnetic resonance imaging (MRI) represents the most promising modality to overcome the limitations of PET/CT. The development of rapid, repeatable MRI techniques to identify and quantify both metabolically active and inactive BAT non-invasively and without the use of exogenous contrast agents or the need for sedation in pediatric patients are critically needed to advance our knowledge of this tissue's physiology.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"SEP","issued":{"date-parts":[["2011"]]},"note":"NULL","page":"1-6","title":"Developments in the imaging of brown adipose tissue and its associations with muscle, puberty, and health in children","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁰","plainTextFormattedCitation":"60","previouslyFormattedCitation":"⁶⁰"},"properties":{"noteIndex":0},"schema":""}60. Therefore, the observed change in MRI FF is thought to be a measure of the primary fuel source for NST, which is unlike 18F-FDG PET/CT. Ultimately, given that FF might not effective at distinguishing between BAT and WAT, an additional MRI parameter is warranted.MRI T2*T2* (or its reciprocal, R2*), which is defined as the decay of transverse magnetization caused by inhomogeneities in the magnetic field (often presented as milliseconds (msec)), is a tissue-specific MRI property that can be used in combination with FF to further differentiate BAT from WAT (see Figure 10 in Appendix Section 7.1 for an excerpt from Hu et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61 showing the unique MRI signatures of BAT-like tissue and WAT-like tissue)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1148/rg.295095034","ISBN":"1527-1323 (Electronic)\\r0271-5333 (Linking)","ISSN":"1527-1323","PMID":"19755604","abstract":"T2* relaxation refers to decay of transverse magnetization caused by a combination of spin-spin relaxation and magnetic field inhomogeneity. T2* relaxation is seen only with gradient-echo (GRE) imaging because transverse relaxation caused by magnetic field inhomogeneities is eliminated by the 180 degrees pulse at spin-echo imaging. T2* relaxation is one of the main determinants of image contrast with GRE sequences and forms the basis for many magnetic resonance (MR) applications, such as susceptibility-weighted (SW) imaging, perfusion MR imaging, and functional MR imaging. GRE sequences can be made predominantly T2* weighted by using a low flip angle, long echo time, and long repetition time. GRE sequences with T2*-based contrast are used to depict hemorrhage, calcification, and iron deposition in various tissues and lesions. SW imaging uses phase information in addition to T2*-based contrast to exploit the magnetic susceptibility differences of the blood and of iron and calcification in various tissues. Perfusion MR imaging exploits the signal intensity decrease that occurs with the passage of a high concentration of gadopentetate dimeglumine through the microvasculature. Change in oxygen saturation during specific tasks changes the local T2*, which leads to the blood oxygen level-dependent effect seen at functional MR imaging. The basics of T2* relaxation, T2*-weighted sequences, and their clinical applications are presented, followed by the principles, techniques, and clinical uses of four T2*-based applications, including SW imaging, perfusion MR imaging, functional MR imaging, and iron overload imaging","author":[{"dropping-particle":"","family":"Chavhan","given":"Govind B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Babyn","given":"Paul S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Bejoy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Manohar M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haacke","given":"E Mark","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Radiographics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009"]]},"page":"1433-1449","publisher":"Radiological Society of North America","title":"Principles, techniques, and applications of T2*-based MR imaging and its special applications","type":"article-journal","volume":"29"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"^61,62","plainTextFormattedCitation":"61,62","previouslyFormattedCitation":"^61,62"},"properties":{"noteIndex":0},"schema":""}61,62. Basally, the abundance of iron-rich mitochondria in BAT accelerates T2* decay to a greater extent than would WAT, translating into lower T2* valuesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1148/rg.295095034","ISBN":"1527-1323 (Electronic)\\r0271-5333 (Linking)","ISSN":"1527-1323","PMID":"19755604","abstract":"T2* relaxation refers to decay of transverse magnetization caused by a combination of spin-spin relaxation and magnetic field inhomogeneity. T2* relaxation is seen only with gradient-echo (GRE) imaging because transverse relaxation caused by magnetic field inhomogeneities is eliminated by the 180 degrees pulse at spin-echo imaging. T2* relaxation is one of the main determinants of image contrast with GRE sequences and forms the basis for many magnetic resonance (MR) applications, such as susceptibility-weighted (SW) imaging, perfusion MR imaging, and functional MR imaging. GRE sequences can be made predominantly T2* weighted by using a low flip angle, long echo time, and long repetition time. GRE sequences with T2*-based contrast are used to depict hemorrhage, calcification, and iron deposition in various tissues and lesions. SW imaging uses phase information in addition to T2*-based contrast to exploit the magnetic susceptibility differences of the blood and of iron and calcification in various tissues. Perfusion MR imaging exploits the signal intensity decrease that occurs with the passage of a high concentration of gadopentetate dimeglumine through the microvasculature. Change in oxygen saturation during specific tasks changes the local T2*, which leads to the blood oxygen level-dependent effect seen at functional MR imaging. The basics of T2* relaxation, T2*-weighted sequences, and their clinical applications are presented, followed by the principles, techniques, and clinical uses of four T2*-based applications, including SW imaging, perfusion MR imaging, functional MR imaging, and iron overload imaging","author":[{"dropping-particle":"","family":"Chavhan","given":"Govind B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Babyn","given":"Paul S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Bejoy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Manohar M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haacke","given":"E Mark","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Radiographics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009"]]},"page":"1433-1449","publisher":"Radiological Society of North America","title":"Principles, techniques, and applications of T2*-based MR imaging and its special applications","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶²","plainTextFormattedCitation":"62","previouslyFormattedCitation":"⁶²"},"properties":{"noteIndex":0},"schema":""}62. During activation, there is a measured decrease in BAT T2* due to the heightened oxygen exchange between saturated (i.e. oxyhemoglobin) and unsaturated (deoxyhemoglobin) iron-containing cellsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. A larger concentration of the latter form of hemoglobin ultimately lowers T2* values from baselineADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1148/rg.295095034","ISBN":"1527-1323 (Electronic)\\r0271-5333 (Linking)","ISSN":"1527-1323","PMID":"19755604","abstract":"T2* relaxation refers to decay of transverse magnetization caused by a combination of spin-spin relaxation and magnetic field inhomogeneity. T2* relaxation is seen only with gradient-echo (GRE) imaging because transverse relaxation caused by magnetic field inhomogeneities is eliminated by the 180 degrees pulse at spin-echo imaging. T2* relaxation is one of the main determinants of image contrast with GRE sequences and forms the basis for many magnetic resonance (MR) applications, such as susceptibility-weighted (SW) imaging, perfusion MR imaging, and functional MR imaging. GRE sequences can be made predominantly T2* weighted by using a low flip angle, long echo time, and long repetition time. GRE sequences with T2*-based contrast are used to depict hemorrhage, calcification, and iron deposition in various tissues and lesions. SW imaging uses phase information in addition to T2*-based contrast to exploit the magnetic susceptibility differences of the blood and of iron and calcification in various tissues. Perfusion MR imaging exploits the signal intensity decrease that occurs with the passage of a high concentration of gadopentetate dimeglumine through the microvasculature. Change in oxygen saturation during specific tasks changes the local T2*, which leads to the blood oxygen level-dependent effect seen at functional MR imaging. The basics of T2* relaxation, T2*-weighted sequences, and their clinical applications are presented, followed by the principles, techniques, and clinical uses of four T2*-based applications, including SW imaging, perfusion MR imaging, functional MR imaging, and iron overload imaging","author":[{"dropping-particle":"","family":"Chavhan","given":"Govind B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Babyn","given":"Paul S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thomas","given":"Bejoy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shroff","given":"Manohar M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haacke","given":"E Mark","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Radiographics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2009"]]},"page":"1433-1449","publisher":"Radiological Society of North America","title":"Principles, techniques, and applications of T2*-based MR imaging and its special applications","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶²","plainTextFormattedCitation":"62","previouslyFormattedCitation":"⁶²"},"properties":{"noteIndex":0},"schema":""}62. Since this MRI parameter overcomes a limitation in FF, T2* serves as a complementary biomarker to improve the detection specificity of BAT and is therefore becoming more commonplaceADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1038/s41598-017-01586-7","ISSN":"20452322","PMID":"28596551","abstract":"Human brown adipose tissue (BAT), with a major site in the cervical-supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervical-supraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R2(*) maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi-automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R2(*) and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice?=?0.93?±?0.03 (mean?±?standard deviation) and correlation coefficients of r?>?0.99 (P?<?0.0001) in FF, R2(*) and volume estimates, between the methods, were observed. Dice and BMI were positively correlated (r?=?0.54, P?=?0.03) but no other significant bias was obtained (P?≥?0.07). The automated method compared well with the reference method and can therefore be suitable for time-efficient and objective measurements in large cohort research studies of BAT.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forslund","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weghuber","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"^58,63,64","plainTextFormattedCitation":"58,63,64","previouslyFormattedCitation":"^58,63,64"},"properties":{"noteIndex":0},"schema":""}58,63,64.Strengths and Limitations Of MRIMRI is a feasible method for assessing BAT activity in a healthy human cohort. Unlike alternatives, such as PET/CT, imaging of BAT using MRI does not require injection of radioactive tracers, does not deliver doses of radiation, and has no limitations in imaging penetration depthADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0074206","author":[{"dropping-particle":"","family":"Branca","given":"Rosa T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Warren S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Auerbach","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khanna","given":"Arjun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Degan","given":"Simone","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ugurbil","given":"Kamil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maronpot","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2013"]]},"page":"e74206","title":"In Vivo Noninvasive Detection of Brown Adipose Tissue through Intermolecular Zero-Quantum MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁵","plainTextFormattedCitation":"65","previouslyFormattedCitation":"⁶⁵"},"properties":{"noteIndex":0},"schema":""}65. Furthermore, MRI FF offers a surrogate measure of fat tissue content within a specified region, which has a proven sensitivity to detect changes in BAT following a stimulus (i.e. a decrease in post-stimulus FF values from baseline levels is well correlated with 18F-FDG uptake, the current reference standard)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.24369","ISBN":"1522-2594 (Electronic)\\r0740-3194 (Linking)","ISSN":"07403194","PMID":"22693111","abstract":"Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding opportunities from the National Institutes of Health.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B?rnert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernando","given":"Diego","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kellman","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Jingfei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeder","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sirlin","given":"Claude","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"378-388","title":"ISMRM workshop on fat-water separation: Insights, applications and progress in MRI","type":"article-journal","volume":"68"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"^66,67","plainTextFormattedCitation":"66,67","previouslyFormattedCitation":"^66,67"},"properties":{"noteIndex":0},"schema":""}66,67. Further, this imaging modality has been validated with histology and immunohistochemistryADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2013-2036","ISSN":"1945-7197","PMID":"24384025","abstract":"OBJECTIVE: Manipulation of human brown adipose tissue (BAT) represents a novel therapeutic option for diabesity. The aim of our study was to develop and test a novel magnetic resonance (MR) imaging-based method to identify human BAT, delineate it from white adipose tissue, and validate it through immunohistochemistry.\\n\\nDESIGN: A 25-year old Caucasian female with hyperparathyroidism-jaw tumor syndrome underwent parathyroidectomy. An (18)fluoro-2-deoxyglucose positron emission tomography (PET)-computed tomography (CT) scan performed after surgery ruled out malignancy but showed avid uptake within the mediastinum, neck, supraclavicular fossae, and axillae, consistent with BAT. Immunohistochemical staining using uncoupling protein-1 antibody was performed on one fat sample obtained from the suprasternal area during parathyroidectomy. Subsequently, serial MR scans were performed. Retrospectively, regions of interest (ROIs) were identified on MR corresponding to areas of high uptake on PET-CT. Prospectively, ROIs were identified on MR based on signal intensity and appearance and compared with PET-CT.\\n\\nRESULTS: Of 111 retrospectively identified ROIs from PET-CT, 93 (83.8%) showed corresponding low MR signal: 25 of 25 mediastinum (100%), 29 of 31 neck (93.5%), 31 of 41 supraclavicular (75.6%), and 8 of 14 axillae (57%). Prospectively, 47 of 54 ROIs identified on MR (87%) showed a corresponding increased uptake on PET-CT. Serendipitously, the sample obtained at surgery corresponded with high uptake and low signal on subsequent PET and MR, respectively, and immunohistochemistry confirmed BAT.\\n\\nCONCLUSION: We provide the first report for the reliable use of MR to identify BAT in a living human adult, with histological/immunohistochemical confirmation. Our data demonstrate proof of concept to support the development of MR as a safe, reproducible imaging modality for human BAT.","author":[{"dropping-particle":"","family":"Reddy","given":"Narendra L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Terence A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wayte","given":"Sarah C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adesanya","given":"Oludolapo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sankar","given":"Sailesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yeo","given":"Yen C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tripathi","given":"Gyanendra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McTernan","given":"Philip G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Randeva","given":"Harpal S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Sudhesh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutchinson","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barber","given":"Thomas M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"E117-E121","title":"Identification of brown adipose tissue using MR imaging in a human adult with histological and immunohistochemical confirmation.","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁸","plainTextFormattedCitation":"68","previouslyFormattedCitation":"⁶⁸"},"properties":{"noteIndex":0},"schema":""}68 and is proven to be a reliable approach to BAT detection in both infantADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0077907","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"24205024","abstract":"There is a major resurgence of interest in brown adipose tissue (BAT) biology, particularly regarding its determinants and consequences in newborns and infants. Reliable methods for non-invasive BAT measurement in human infants have yet to be demonstrated. The current study first validates methods for quantitative BAT imaging of rodents post mortem followed by BAT excision and re-imaging of excised tissues. Identical methods are then employed in a cohort of in vivo infants to establish the reliability of these measures and provide normative statistics for BAT depot volume and fat fraction. Using multi-echo water-fat MRI, fat- and water-based images of rodents and neonates were acquired and ratios of fat to the combined signal from fat and water (fat signal fraction) were calculated. Neonatal scans (n = 22) were acquired during natural sleep to quantify BAT and WAT deposits for depot volume and fat fraction. Acquisition repeatability was assessed based on multiple scans from the same neonate. Intra- and inter-rater measures of reliability in regional BAT depot volume and fat fraction quantification were determined based on multiple segmentations by two raters. Rodent BAT was characterized as having significantly higher water content than WAT in both in situ as well as ex vivo imaging assessments. Human neonate deposits indicative of bilateral BAT in spinal, supraclavicular and axillary regions were observed. Pairwise, WAT fat fraction was significantly greater than BAT fat fraction throughout the sample (ΔWAT-BAT = 38 %, p<10(-4)). Repeated scans demonstrated a high voxelwise correlation for fat fraction (Rall = 0.99). BAT depot volume and fat fraction measurements showed high intra-rater (ICCBAT,VOL = 0.93, ICCBAT,FF = 0.93) and inter-rater reliability (ICCBAT,VOL = 0.86, ICCBAT,FF = 0.93). This study demonstrates the reliability of using multi-echo water-fat MRI in human neonates for quantification throughout the torso of BAT depot volume and fat fraction measurements.","author":[{"dropping-particle":"","family":"Rasmussen","given":"Jerod M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Entringer","given":"Sonja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nguyen","given":"Annie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erp","given":"Theo G M","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guijarro","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oveisi","given":"Fariba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swanson","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piomelli","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wadhwa","given":"Pathik D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buss","given":"Claudia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potkin","given":"Steven G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013"]]},"title":"Brown adipose tissue quantification in human neonates using water-fat separated MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁹","plainTextFormattedCitation":"69","previouslyFormattedCitation":"⁶⁹"},"properties":{"noteIndex":0},"schema":""}69 and adultADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3444","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"26620447","abstract":"The supraclavicular fat depot is known for brown adipose tissue presence. To unravel adipose tissue physiology and metabolism, high quality and reproducible imaging is required. In this study we quantified the reliability and agreement of MRI fat fraction measurements in supraclavicular and subcutaneous adipose tissue of 25 adult patients with clinically manifest cardiovascular disease. MRI fat fraction measurements were made under ambient temperature conditions using a vendor supplied mDixon chemical-shift water-fat multi-echo pulse sequence at 1.5 T field strength. Supraclavicular fat fraction reliability (intraclass correlation coefficientagreement , ICCagreement ) was 0.97 for test-retest, 0.95 for intra-observer and 0.56 for inter-observer measurements, which increased to 0.88 when ICCconsistency was estimated. Supraclavicular fat fraction agreement displayed mean differences of 0.5% (limit of agreement (LoA) -1.7 to 2.6) for test-retest, -0.5% (LoA -2.9 to 2.0) for intra-observer and 5.6% (LoA 0.4 to 10.8) for inter-observer measurements. Median fat fraction in supraclavicular adipose tissue was 82.5% (interquartile range (IQR) 78.6-84.0) and 89.7% (IQR 87.2-91.5) in subcutaneous adipose tissue (p < 0.0001). In conclusion, water-fat MRI has good reliability and agreement to measure adipose tissue fat fraction in patients with manifest cardiovascular disease. These findings enable research on determinants of fat fraction and enable longitudinal monitoring of fat fraction within adipose tissue depots. Interestingly, even in adult patients with manifest cardiovascular disease, supraclavicular adipose tissue has a lower fat fraction compared with subcutaneous adipose tissue, suggestive of distinct morphologic characteristics, such as brown adipose tissue. Copyright (c) 2015 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikendal","given":"Anouk L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR in Biomedicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"48-56","title":"Reliability and agreement of adipose tissue fat fraction measurements with water-fat MRI in patients with manifest cardiovascular disease","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁷","plainTextFormattedCitation":"57","previouslyFormattedCitation":"⁵⁷"},"properties":{"noteIndex":0},"schema":""}57 humans.Nonetheless, MRI does have limitations – namely, the spatial resolution of approximately 1mm3 is susceptible to “partial volume effects” as data from different types of cells (for example, in SCV BAT, where there is a mixture of WAT, BAT, muscle, and blood vessels) are often captured within the same voxel, leading to false positive and false negative findingsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0074206","author":[{"dropping-particle":"","family":"Branca","given":"Rosa T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Warren S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Auerbach","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khanna","given":"Arjun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Degan","given":"Simone","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ugurbil","given":"Kamil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maronpot","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2013"]]},"page":"e74206","title":"In Vivo Noninvasive Detection of Brown Adipose Tissue through Intermolecular Zero-Quantum MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁵","plainTextFormattedCitation":"65","previouslyFormattedCitation":"⁶⁵"},"properties":{"noteIndex":0},"schema":""}65. Furthermore, MRI is extremely susceptible to motion artefacts as even the slightest movement between or during scans make image registration and delineation of anatomical borders less precise. That said, two images of the same individual taken minutes apart might appear entirely different if one’s position has changed. Lastly, whole-body acquisitions using the IDEAL sequence are not possible and therefore images at a given time point are limited to a predefined field of view.Current state of the literature in humansAs previously mentioned, mild cold exposure is the most potent activator of NST in humans. There are over 80 studies to date which have reported using cold exposure to activate BAT in human subjects. Among these, investigators have used various combinations of cooling methods and imaging modalities to capture the morphological and physiological changes in BAT. The potential implications of this lack of standardization was addressed in a review article by van der Lans et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"103-113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁹","plainTextFormattedCitation":"49","previouslyFormattedCitation":"⁴⁹"},"properties":{"noteIndex":0},"schema":""}49 Despite these inconsistencies, MRI is becoming increasingly utilized to garner insight into the physiological changes associated with NST. So far, approximately 12 studies have combined cold exposure and MRI in humans, 9 of which have been published since 2015. Nonetheless, the notable heterogeneity among methodologies, particularly concerning cold exposure which has been delivered via a temperature-controlled room or a water-perfused garment at varying durations and intensitiesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ijo.2015.94","ISSN":"0307-0565","author":[{"dropping-particle":"","family":"Rachid","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodovalho","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Folli","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beltramini","given":"G C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morari","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amorim","given":"B J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pedro","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramalho","given":"A F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombassaro","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tincani","given":"AJ","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaim","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pareja","given":"JC","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geloneze","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"CD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cendes","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"MJA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velloso","given":"LA","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-4","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.mri.2013.10.003","ISBN":"1873-5894","ISSN":"1873-5894","PMID":"24239336","abstract":"PURPOSE To report the observation of brown adipose tissue (BAT) with low fat content in neonates with hypoxic-ischemic encephalopathy (HIE) after they have undergone hypothermia therapy. MATERIALS AND METHODS The local ethics committee approved the imaging study. Ten HIE neonates (3 males, 7 females, age range: 2-3days) were studied on a 3-T MRI system using a low-flip-angle (3°) six-echo proton-density-weighted chemical-shift-encoded water-fat pulse sequence. Fat-signal fraction (FF) measurements of supraclavicular and interscapular (nape) BAT and adjacent subcutaneous white adipose tissues (WAT) were compared to those from five non-HIE neonates, two recruited for the present investigation and three from a previous study. RESULTS In HIE neonates, the FF range for the supraclavicular, interscapular, and subcutaneous regions was 10.3%-29.9%, 28.0%-57.9%, and 62.6%-88.0%, respectively. In non-HIE neonates, the values were 23.7%-42.2% (p=0.01), 45.4%-59.5% (p=0.06), and 67.8%-86.3% (p=0.38), respectively. On an individual basis, supraclavicular BAT FF was consistently the lowest, interscapular BAT values were higher, and subcutaneous WAT values were the highest (p<0.01). CONCLUSION We speculate that hypothermia therapy in HIE neonates likely promotes BAT-mediated non-shivering thermogenesis, which subsequently leads to a depletion of the tissue's intracellular fat stores. We believe that this is consequently reflected in lower FF values, particularly in the supraclavicular BAT depot, in contrast to non-HIE neonates.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Tai-Wei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yin","given":"Larry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Mimi S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic resonance imaging","id":"ITEM-5","issue":"2","issued":{"date-parts":[["2014"]]},"page":"107-17","title":"MRI detection of brown adipose tissue with low fat content in newborns with hypothermia.","type":"article-journal","volume":"32"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-6","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]},{"id":"ITEM-7","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-7","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]},{"id":"ITEM-8","itemData":{"DOI":"10.2967/jnumed.112.117275.Measurement","author":[{"dropping-particle":"","family":"Chen","given":"Yin-Ching Iris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Yih-Chieh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C Ronald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"Kenneth K","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-8","issue":"9","issued":{"date-parts":[["2013"]]},"page":"1584-1587","title":"Measurement of Human Brown Adipose Tissue Volume and Activity Using Anatomical MRI and Functional MRI","type":"article-journal","volume":"54"},"uris":[""]},{"id":"ITEM-9","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-9","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-10","itemData":{"DOI":"10.1016/j.metabol.2017.02.001","ISSN":"00260495","PMID":"28403942","author":[{"dropping-particle":"","family":"Holstila","given":"Milja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pesola","given":"Marko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"Ronald J.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism","id":"ITEM-10","issued":{"date-parts":[["2017"]]},"page":"23-30","publisher":"Elsevier Inc.","title":"MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure","type":"article-journal","volume":"70"},"uris":[""]},{"id":"ITEM-11","itemData":{"DOI":"10.1111/dom.12433","ISBN":"1463-1326 (Electronic) 1462-8902 (Linking)","ISSN":"14631326","PMID":"25586670","abstract":"The aim of the present study was to determine whether single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) can non-invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using (18)F-fluorodeoxyglucose positron emission tomography (PET) and (15)O-H2O PET perfusion during cold exposure, and (1)H-MRS at ambient temperature. Image-guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by (1)H-MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8-year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M-value; euglycaemic-hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76-95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by (1)H-MRS may be an independent marker of whole-body insulin sensitivity, independent of brown adipose tissue metabolic activation.","author":[{"dropping-particle":"","family":"Raiko","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holstila","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"K. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Orava","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Niemi","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laine","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taittonen","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"R. J H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes, Obesity and Metabolism","id":"ITEM-11","issue":"5","issued":{"date-parts":[["2015"]]},"page":"516-519","title":"Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity","type":"article-journal","volume":"17"},"uris":[""]},{"id":"ITEM-12","itemData":{"DOI":"10.1016/j.metabol.2016.03.012","ISBN":"1532-8600 (Electronic) 0026-0495 (Linking)","ISSN":"15328600","PMID":"27173471","abstract":"Objective. To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze. Design Randomized, open, parallel-group trial. Methods. Healthy non-selected participants were randomized to achieve cold-exposure 1 hour/day, or to avoid any sense of feeling cold, for 6 weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI). Results. Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841 ?? 199 kCal/24 h to 1795 ?? 213 kCal/24 h, p = 0.047 cold-activated MR from 1900 ?? 150 kCal/24 h to 1793 ?? 215 kCal/24 h, p = 0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p = 0.052). The difference between MR changes by the interventions between groups was statistically significant (p = 0.008 at room temperature, p = 0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported ??? 8 days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175 ?? 0.015 l to 0.0216 ?? 0.014 l, p = 0.049). Conclusions. We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans.","author":[{"dropping-particle":"","family":"Romu","given":"Thobias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vavruch","given":"Camilla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dahlqvist-Leinhard","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tallberg","given":"Joakim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dahlstr??m","given":"Nils","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Persson","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heglind","given":"Mikael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lidell","given":"Martin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enerb??ck","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borga","given":"Magnus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nystrom","given":"Fredrik H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism: Clinical and Experimental","id":"ITEM-12","issue":"6","issued":{"date-parts":[["2016"]]},"page":"926-934","publisher":"The Authors","title":"A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans","type":"article-journal","volume":"65"},"uris":[""]},{"id":"ITEM-13","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-13","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"^{38,55,56,58,63,67,70–76}","plainTextFormattedCitation":"38,55,56,58,63,67,70–76","previouslyFormattedCitation":"^{38,55,56,58,63,67,70–76}"},"properties":{"noteIndex":0},"schema":""}38,55,56,58,63,67,70–76, makes an approach to knowledge synthesis unfeasible. These differences aside, results have been unanimous in that cooling elicits a significant decrease in MRI-derived BAT FF (mean ΔFF between -0.4% and -5% in healthy adult populations)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.metabol.2017.02.001","ISSN":"00260495","PMID":"28403942","author":[{"dropping-particle":"","family":"Holstila","given":"Milja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pesola","given":"Marko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"Ronald J.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"23-30","publisher":"Elsevier Inc.","title":"MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure","type":"article-journal","volume":"70"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-3","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-4","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-5","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"^{55,56,58,63,70}","plainTextFormattedCitation":"55,56,58,63,70","previouslyFormattedCitation":"^{55,56,58,63,70}"},"properties":{"noteIndex":0},"schema":""}55,56,58,63,70.However, few studiesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-2","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"^56,74","plainTextFormattedCitation":"56,74","previouslyFormattedCitation":"^56,74"},"properties":{"noteIndex":0},"schema":""}56,74 have taken advantage of arguably the most attractive feature of MRI – it’s safety. In other words, an absence of ionizing radiation or radioactive tracers permits repeat scanning in the same subjects. Rather than limiting one’s findings to pre- and post-cold measures of BAT, gathering data at defined intervals throughout the cold exposure can translate into a time course (or time series) plot of BAT-specific MRI measures. Time course studies using MRI are expected to inform about the physiological response of cold-induced BAT in the context of intracellular TAG use (i.e. decline in FF), and may assist in refining cold-exposure protocols according to when and how maximal BAT activity is captured by MRI.BAT Time Course Evidence to DateAs stated in a seminal review by Cannon and Nedergaard, early research measuring continuous NE turnover in rats suggested that “bouts” of BAT activity may be much shorter than several hoursADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. However, the time course of this process has still not been highlighted by the available literature. Given that intracellular TAGs are the primary fuel for BAT NST, MRI FF is a preferred modality to uncover such evidence. In 2013, Hu et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.24053","ISBN":"1522-2586 (Electronic) 1053-1807 (Linking)","ISSN":"10531807","PMID":"23440739","abstract":"PURPOSE To compare fat-signal fractions (FFs) and T2* values between brown (BAT) and white (WAT) adipose tissue located within the supraclavicular fossa and subcutaneous depots, respectively. MATERIALS AND METHODS Twelve infants and 39 children were studied. Children were divided into lean and overweight/obese subgroups. Chemical-shift-encoded water-fat magnetic resonance imaging (MRI) was used to quantify FFs and T2* metrics in the supraclavicular and adjacent subcutaneous adipose tissue depots. Linear regression and t-tests were performed. RESULTS Infants had lower supraclavicular FFs than children (P < 0.01) but T2* values were similar (P = 0.5). Lean children exhibited lower supraclavicular FFs and T2* values than overweight children (P < 0.01). In each individual infant and child, supraclavicular FFs were consistently lower than adjacent subcutaneous FFs. Supraclavicular T2* values were consistently lower than subcutaneous T2* values in children, but not in infants. FFs in both depots were positively correlated with age and weight in infants (P < 0.01). In children, they were correlated with weight and body mass index (BMI) (P < 0.01), but not age. Correlations between T2* and anthropometric variables existed in children (P < 0.01), but were absent in infants. CONCLUSION Cross-sectional comparisons suggest variations in FF and T2* values in the supraclavicular and subcutaneous depots of infants and children, which are potentially indicative of physiological differences in adipose tissue fat content, amount, and metabolic activity.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yin","given":"Larry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggabao","given":"Patricia C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013"]]},"page":"885-896","title":"Comparison of brown and white adipose tissues in infants and children with chemical-shift-encoded water-fat MRI","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁷","plainTextFormattedCitation":"77","previouslyFormattedCitation":"⁷⁷"},"properties":{"noteIndex":0},"schema":""}77 challenged the research community to implement a MRI protocol that characterizes FF dynamically using a paradigm that stimulates BAT, such as cold. Deng et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 similarly recommended a continuous measurement of FF during a period of acute deactivation (i.e. warming) to investigate the potential restoration of these values, which is even less described than cooling. Though scarce, a continuous assessment of various aspects of BAT response to cold have been integrated in both human and animal research and these studies are summarized in Appendix Section 7.1, Tables 7 (humans) and 8 (animals) on page 60.Summary of Time Course EvidenceAlthough establishing the time course of BAT activity was not a primary objective of many of these studies, they have noted that BAT-specific responses in humans (i.e. time to nadir FF, 11C-acetate radioactivity, functional MRI (fMRI) signal in the hypothalamus, or SCV skin temperature) are immediate but transient (~ 60 minutes).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel 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Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1172/JCI60433DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"00219738 15588238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis 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Journal of Obesity","id":"ITEM-3","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark 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independent studies have explored the time course of MRI-derived BAT FF during cooling in human subjects.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-2","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"^56,74","plainTextFormattedCitation":"56,74","previouslyFormattedCitation":"^56,74"},"properties":{"noteIndex":0},"schema":""}56,74 Though each group contributed novel evidence to this field of research, there were notable limitations in their methodologies. Specifically, Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 selected a small square ROI in the interscapular region (ie. iBAT) of their subjects (5 males and 5 females under the age of 30, all with a normal BMI), an area not commonly associated with active BAT in human adults. Further, the researchers used distinct ROI selection criterion for each temperature phase (i.e. different FF thresholding for baseline, cold, and warm exposures), and were selective for only those FF voxels which produced a negative gradient during cooling. Though they scanned and presented data on the iBAT, WAT, and muscle of subjects every five minutes during cooling (90 minutes at 12°C) and subsequent warming (30 minutes at 37°C), they delivered these exposures using a water-perfused vest which does not cover the entire bodyADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.22162.","ISBN":"8585348585","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"DL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"KS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goran","given":"MI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy","given":"TR","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2010"]]},"page":"1195-1202","title":"Identification of Brown Adipose Tissue in Mice with Fat-Water IDEAL-MRI","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵³","plainTextFormattedCitation":"53","previouslyFormattedCitation":"⁵³"},"properties":{"noteIndex":0},"schema":""}53. McCallister et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁴","plainTextFormattedCitation":"74","previouslyFormattedCitation":"⁷⁴"},"properties":{"noteIndex":0},"schema":""}74 garnered SCV BAT FF measurements from seven subjects (males and females of all ages and BMI categories) during a 2.5-hour cold exposure distributed via water-perfused pads. ROI selection within the SCV was based on MRI-derived anatomical maps and areas of high intensity 18F-FDG uptake (i.e. to remove tissue that does not exhibit “BAT-like” properties), which was a notable strength. However, this group chose to scan at 30 to 40-minute intervals throughout the 2.5-hour cold exposure, resulting in only 4-5 time points. Lastly, changes in SCV BAT FF were not accompanied by comparator regions such as subcutaneous WAT or muscle, which would have added completeness to the results. Given this paucity of data, studies with added methodological rigor are warranted.STUDY RATIONALE AND OBJECTIVESRationale and SignificanceOur understanding of BAT activity in humans is currently limited to measurements of thermogenesis before and after a stimulus. In light of the evidence presented in Appendix Section 7.1, Tables 7 and 8, the research community might be neglecting key evidence concerning the time course of fuel utilization during NST. Since MRI provides a surrogate measurement of tissue TAG content that is sensitive to cold-induced thermogenesis, coupled with the ability to repeat scans in healthy and young human subjects, it is a preferred modality to uncover such evidence. In capturing these “real time” changes, findings might reveal that a cooling duration in the range of 2-3 hours is not necessary. Though a few groups have published evidence concerning this exact notion, there were notable shortcomings in each of their methodologies. As such, a protocol involving uniform whole-body mild cold exposure and subsequent warming, scanning at defined intervals to obtain measurements of FF, and a BAT ROI that is consistently reported in the literature will contribute to new knowledge.Overarching PurposeTo describe the patterns of change in SCV BAT FF during a 3-hour mild cold exposure (18°C) followed by a 30-minute warm exposure (32°C) in a cohort of adult males under the age of 30.Objectives and HypothesesObjectivesTo identify the pattern of change in SCV BAT FF during a 3-hour mild cold exposure (18°C).What is the time course of change in SCV BAT FF during cooling?How do the rate and magnitude of change in SCV BAT FF vary over the period of cold exposure?What is the earliest time point at which a significant change in FF occurs in BAT? What is the earliest time point where changes no longer differ from the 180-minute value?How can the change in SCV BAT FF over the course of time be modeled mathematically?What is the pattern of change in an adipose tissue region with unknown thermogenic properties?To evaluate if indices of body composition are related to the pattern of cold-induced change in SCV BAT FF within this small cohort of male adults.Are factors previously shown to be related to BAT activity correlated with the pattern of response to cold over time?To identify the patterns of change in SCV BAT FF during a 30-minute warm exposure (32°C).What is the time course of change in SCV BAT FF during warming?HypothesesI hypothesize cold exposure to elicit an immediate but transient decrease in SCV BAT FF. I also hypothesize the adipose tissue region which is presumably devoid of thermogenic function to exhibit no measurable cold-induced changes in FF. I hypothesize BMI and % body fat to be negatively related to the magnitude of change in BAT FF throughout the time course.I hypothesize that warm exposure (i.e. BAT deactivation) will recover FF towards the baseline value.METHODSStudy Design and PopulationHealthy adult males between the ages of 18 to 29 years old were prospectively recruited from McMaster University and the surrounding Hamilton Community (e.g. Mohawk college, businesses, recreation and fitness centers, and hospitals) using posters, internal media advertising, social media postings, and through referrals by active/past participants and/or fellow members of the research team. All participants completed two visits – (i) Initial Visit: Collection of anthropometric and body composition measurements; and (ii) Time Course MRI Session: Collection of BAT measurements. The study was approved by the joint Research Ethics Board of McMaster University and Hamilton Health Sciences and all aspects of the study were performed in accordance with that approval. Enrolled participants provided informed, signed consent. Exclusion criteria, subject preparation, and conditions used in the study can be found in Table 1.Table SEQ Table \* ARABIC 1 - Criteria and conditions used in the studyEXCLUSION CRITERIAFemale sexUnder the age of 18 or over the age of 30Self-reported alcohol intake greater than 7 drinks/week with no more than 3 drinks/day Use of any of the following medications (β adrenergic, steatogenic, anti-hyperglycemic, antidepressant, anxiolytic, anti-psychotic, thyroid, antiemetic – 5HT3 antagonists or serotonergic drugs)?Tobacco and/or nicotine use (smoking, nicotine patch, chew tobacco, nicotine gum, e-cigarette or cigar)Any contraindications for MRI (claustrophobia, implanted metal, metallic injuries recent tattoo or weight>300lb)Prior bariatric surgery or liver transplantationAny conditions associated with brown adipose tissue, hepatic steatosis or liver disorders?CHARACTERISTICSCRITERIA AND CONDITIONS IN STUDYSubject Preparation for Both VisitsMeals 24 hours before visitAvoid the following serotonergic foods: tomato, plum, kiwi, avocado, banana, pineapple, walnutsCaffeine before visitNo caffeine 12 hours before visitFast duration before visit8-12 hoursStrenuous activity within 48 hours of visitNoneConditions (Time Course MRI Session)MRI room temperature19-21°CTime of visitBetween 0745 and 1000 hoursTime of yearSummer, fall, and winterOutdoor temperature range-12.2°C to 18.9°CMRI scanning frequencyCooling: Every 5 minutes during the first 60 minutes, and every 15 minutes thereafter; Warming: Every 5 minutesCooling/Warming Protocol (Time Course MRI Session)Exposure paradigmFixedExposure locationMRI roomExposure deviceLiquid-conditioned cooling garment (LCS; Two Piece, Allen-Vanguard, Ottawa, ON, Canada)Cooling temperature18°CWarming temperature32°CTotal duration of cooling180 minutesTotal duration of warming30 minutesMethod used to monitor inlet and outlet water temperaturesFiber-optic temperature probes (FO Temp Sensor, Polymide Tip, Neoptix, Qualitrol, Quebec, Canada) and data logger system (Model RFX273A, Neoptix, Quebec, Canada).Method used to monitor skin temperatureNoneMethod used to monitor shivering objectivelyNone?for a complete list of excluded medications and medical conditions, refer to Appendix Section 7.2.1Study VisitsInitial VisitParticipants first consented to the study and were then re-screened for eligibility (initial screening was done during the recruitment phase). Anthropometrics (i.e. height, weight and waist circumference) and body composition using Dual Emission X-Ray Absorptiometry (DXA) were then measured, which are described in further detail below. See Appendix Section 7.2.3 for the full visit timeline.Time Course MRI SessionThe time course MRI session occurred within 30 days of the initial visit. This visit began with participants acclimatizing to room temperature (~21°C) for 30 minutes while wearing standardized clothing (light sleeveless t-shirt and shorts). Immediately following, participants changed into the liquid-conditioned suit and were instructed to lay in a supine position on the MRI scanning table. All subjects were provided with visual and audio entertainment throughout the cooling and warming paradigms using a MR-safe rear projection system. The fan which circulates air through the bore of the MR magnet was turned off as to avoid augmenting the intensity of the temperature challenge. Cooling began once the participant was in a comfortable position. Scans were acquired at 5-minute intervals during the first 15 minutes of cooling and every 15 minutes thereafter for the first participant. For the second participant, scanning occurred every 5 minutes during the first 30 minutes of cooling and every 15 minutes thereafter. Following the collection and analysis of data for these two subjects, a protocol was established in which scans were to be acquired every 5 minutes for the first 60 minutes of cold exposure, and every 15 minutes until the 180-minute time point was reached. Upon completion of this phase, participants were warmed for 30 minutes and neck MRI scans were again acquired every 5 minutes. See Figures 12 and 13 in Appendix Section 7.2.3 for the visit timeline and illustration of the equipment setup, respectively.Study ProceduresCold and Warm ExposuresA standardized, uniform, whole-body cold and warm exposure protocol was delivered using a specially designed liquid-conditioned cooling garment (LCS; Two Piece, Allen-Vanguard, Ottawa, ON, Canada) which covered a subject’s entire body except their hands, feet, and head. The same suit was used for all participants to ensure consistent tubing density and water flow. In brief, water was pre-cooled to 18°C using a self-regulating bath (IsoTemp 6200R28, Fisher Scientific, Ottawa, Canada) and delivered to the suit via insulated tubing extensions for up to 180 minutes. This cooling protocol is sufficient to detect BAT activity without significantly decreasing core body temperatureADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"00219738 15588238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical investigation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"545","title":"Brown adipose tissue oxidative metabolism contributles to energy expenditure during cold exposure in humans","type":"article-journal","volume":"122"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2013-3901","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"19457197","PMID":"24423363","abstract":"Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild-cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes (T2D), which may have important pathological and therapeutic implications. Although, many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: To determine whether four weeks of daily cold exposure could increase both the volume of metabolically active brown adipose tissue (BAT) and its oxidative capacity. Design: Six non-acclimated men were exposed to 10°C, two hours daily for four weeks (5 days/week), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with (11)C-acetate and (18)F-fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake and volume prior to and following four weeks of cold acclimation were examined under controlled acute cold exposure conditions. Results: The four-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66±30 to 95±28 mL, P<0.05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725±0.300 to 1.591±0.326 mL·sec(-1), P<0.05). Shivering intensity was not significantly different pre- compared to post-acclimation (2.1±0.7 vs 2.0±0.5 %MVC, respectively). Fractional glucose uptake in BAT increased post-acclimation (from 0.035±0.014 to 0.048±0.012 min(-1)) while net glucose uptake trended towards an increase as well (from 163±60 to 209±50 nmol·g(-1)·min(-1)). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT, but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology & Metabolism","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2014"]]},"page":"438-446","title":"Increased Brown Adipose Tissue Oxidative Capacity in Cold-Acclimated Humans","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"^19,20,78","plainTextFormattedCitation":"19,20,78","previouslyFormattedCitation":"^19,20,78"},"properties":{"noteIndex":0},"schema":""}19,20,78. The water initially increased in temperature (due to the subject’s “warmer” pre-cold skin temperature and the uncooled water within the suit’s tubing), however the exposure stabilized to 18°C after 10-15 minutes. Immediately following the cessation of cooling, the same water-perfused cooling garment was connected to a separate water bath set at 32°C (VWR, Avantor, Randor, USA) for a duration of 30 minutes. Inlet-OutletTwo fiber-optic temperature probes (FO Temp Sensor, Polymide Tip, Neoptix, Qualitrol, Quebec, Canada) were fixed to the tubing extension-suit interface (i.e. manifold system) and transmitted the inlet (i.e. water delivered to the suit) and outlet (i.e. water leaving the suit) temperatures to a data logger system (Model RFX273A, Neoptix, Quebec, Canada). Neolink software (Neoptix, Quebec, Canada) recorded temperature measurements throughout the cold and warm exposures in 15-second intervals. This measurement was obtained for six consecutive participants, and its purpose was to ensure standardization of the cold exposure protocol as the inlet-outlet difference is an indirect measurement of one’s whole-body thermogenic response to a temperature challenge.Primary Outcome MeasureSCV BAT FF (defined below) measured at defined intervals throughout the cooling and warming phases was the primary outcome of interest.MRI Acquisition and Segmentation of the SCV RegionAll MRI scans were performed using a 3-Tesla whole-body MRI scanner (Discovery 750; GE Healthcare, Waukesha, WI, USA) located within the Imaging Research Centre at St. Joseph’s Healthcare Hamilton. BAT MRI scans were acquired with the IDEAL sequence in the axial plane using a Head/Neck/Chest coil. In brief, IDEAL generates FF and T2* maps while accounting for T2* decay and the multiple spectral peaks of fatADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.24369","ISBN":"1522-2594 (Electronic)\\r0740-3194 (Linking)","ISSN":"07403194","PMID":"22693111","abstract":"Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding opportunities from the National Institutes of Health.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B?rnert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernando","given":"Diego","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kellman","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Jingfei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeder","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sirlin","given":"Claude","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"378-388","title":"ISMRM workshop on fat-water separation: Insights, applications and progress in MRI","type":"article-journal","volume":"68"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁶","plainTextFormattedCitation":"66","previouslyFormattedCitation":"⁶⁶"},"properties":{"noteIndex":0},"schema":""}66. This pulse sequence generates six distinct image contrasts: water-only, fat-only, in-phase, out-of-phase, FF and R2* images. To ensure that the entire neck and SCV region were captured, image acquisition started at the C2/C3 disc and ended at the T4/T5 disc. MRI parameters specific to this procedure are included in Appendix Section 7.2.4. Image analysis was performed on Analyze Pro (Version 1; Mayo Clinic, Biomedical Imaging Resource, AnalyzeDirect, Overland Park, KS, USA). All adipose tissue bound by the sternocleidomastoid medially, trapezius posteriorly, and clavicle inferiorly at each of the axial slices between the C5-C6 and T1-T2 discs were manually segmentedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.24053","ISBN":"1522-2586 (Electronic) 1053-1807 (Linking)","ISSN":"10531807","PMID":"23440739","abstract":"PURPOSE To compare fat-signal fractions (FFs) and T2* values between brown (BAT) and white (WAT) adipose tissue located within the supraclavicular fossa and subcutaneous depots, respectively. MATERIALS AND METHODS Twelve infants and 39 children were studied. Children were divided into lean and overweight/obese subgroups. Chemical-shift-encoded water-fat magnetic resonance imaging (MRI) was used to quantify FFs and T2* metrics in the supraclavicular and adjacent subcutaneous adipose tissue depots. Linear regression and t-tests were performed. RESULTS Infants had lower supraclavicular FFs than children (P < 0.01) but T2* values were similar (P = 0.5). Lean children exhibited lower supraclavicular FFs and T2* values than overweight children (P < 0.01). In each individual infant and child, supraclavicular FFs were consistently lower than adjacent subcutaneous FFs. Supraclavicular T2* values were consistently lower than subcutaneous T2* values in children, but not in infants. FFs in both depots were positively correlated with age and weight in infants (P < 0.01). In children, they were correlated with weight and body mass index (BMI) (P < 0.01), but not age. Correlations between T2* and anthropometric variables existed in children (P < 0.01), but were absent in infants. CONCLUSION Cross-sectional comparisons suggest variations in FF and T2* values in the supraclavicular and subcutaneous depots of infants and children, which are potentially indicative of physiological differences in adipose tissue fat content, amount, and metabolic activity.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yin","given":"Larry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggabao","given":"Patricia C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013"]]},"page":"885-896","title":"Comparison of brown and white adipose tissues in infants and children with chemical-shift-encoded water-fat MRI","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁷","plainTextFormattedCitation":"77","previouslyFormattedCitation":"⁷⁷"},"properties":{"noteIndex":0},"schema":""}77. Since the SCV region is heterogenous in morphology, a 30-100% FF threshold and 2-25msec T2* threshold were applied to exclude “non-BAT-like” tissue from future analysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61. This approach is conceptually similar to fusing 18F-FDG PET images with MRI FF maps and segmenting only the SCV tissue within a defined FF range and with a high intensity of radiotracer uptake (i.e. two-stage thresholding)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2967/jnumed.115.160770","ISSN":"0161-5505","PMID":"26272809","abstract":"UNLABELLED: The purpose of the study was to evaluate signal-fat-fraction (SFF) analysis based on a 2-point-Dixon water-fat separation method in whole-body simultaneous PET/MR imaging for identifying brown adipose tissue (BAT) and discriminating it from white adipose tissue (WAT) using cross-validation via PET.\\n\\nMETHODS: This retrospective, internal review board-approved study evaluated 66 PET/MR imaging examinations of 33 pediatric patients (mean age, 14.7 y; range, 7.4-21.4 y). Eleven elderly patients were evaluated as controls (mean age, 79.9 y; range, 76.3-88.6 y). Pediatric patients were divided into 2 groups: with and without metabolically active supraclavicular BAT. The standard of reference for the presence of BAT was at least 1 PET examination showing (18)F-FDG uptake. PET/MR imaging included a 2-point Dixon water-fat separation method. Signal intensities in regions of interest on fat and water images and mean standardized uptake values (SUVmean) were determined bilaterally in supraclavicular and gluteal fat depots. SFF was calculated from the ratio of fat signal over summed water and fat signal. Statistical analysis was conducted using the Student t test and correlation analysis.\\n\\nRESULTS: SFF was significantly lower (P < 0.0001) in supraclavicular BAT than gluteal WAT in all pediatric subjects. Supraclavicular SFF was significantly higher in the control than in the pediatric group (P < 0.0001). In PET-positive patients with multiple examinations, SFF stayed stable whereas SUVmean fluctuated (median intraindividual change, 5% vs. 91%). No significant correlation between SUVmean and SFF could be observed for BAT.\\n\\nCONCLUSION: The results demonstrate that MR imaging-SFF analysis is a reproducible imaging modality for the detection of human BAT and discrimination from WAT. SFF values of BAT are independent from its metabolic activity, making SFF a more reliable parameter for BAT than the commonly used PET signal. However, with the intent to investigate both the composition of BAT and its activation status, hybrid PET/MR imaging might provide supplemental information.","author":[{"dropping-particle":"","family":"Franz","given":"D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karampinos","given":"D. C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rummeny","given":"E. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Souvatzoglou","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beer","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nekolla","given":"S. G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwaiger","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eiber","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-2","issue":"11","issued":{"date-parts":[["2015"]]},"page":"1742-1747","title":"Discrimination Between Brown and White Adipose Tissue Using a 2-Point Dixon Water-Fat Separation Method in Simultaneous PET/MRI","type":"article-journal","volume":"56"},"uris":[""]}],"mendeley":{"formattedCitation":"^54,74","plainTextFormattedCitation":"54,74","previouslyFormattedCitation":"^54,74"},"properties":{"noteIndex":0},"schema":""}54,74. Further, the outer boarder of each ROI was eroded to mitigate any inherent partial volume effects. All voxels that fell within this set of criteria were considered to be SCV BAT, and the average FF value for each scan (i.e. time point) was considered going forward. Changes to the posterior neck subcutaneous adipose tissue (SAT) FF, a region which is presumably devoid of thermogenic function in adult humans, was measured alongside SCV BATADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db12-1430","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"23704519","abstract":"We will review information about and present hypotheses as to the anatomy of brown adipose tissue (BAT). Why is it located where it is in humans? Its anatomical distribution is likely to confer survival value by protecting critical organs from hypothermia by adaptive thermogenesis. Ultimately, the location and function will be important when considering therapeutic strategies for preventing and treating obesity and type 2 diabetes, in which case successful interventions will need to have a significant effect on BAT function in subjects living in a thermoneutral environment. In view of the diverse locations and potential differences in responsiveness between BAT depots, it is likely that BAT will be shown to have much more subtle and thus previously overlooked functions and regulatory control mechanisms.","author":[{"dropping-particle":"","family":"Sacks","given":"Harold","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Symonds","given":"Michael E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2013"]]},"page":"1783-1790","title":"Anatomical locations of human brown adipose tissue: Functional relevance and implications in obesity and type 2 diabetes","type":"article-journal","volume":"62"},"uris":["",""]}],"mendeley":{"formattedCitation":"⁷⁹","plainTextFormattedCitation":"79","previouslyFormattedCitation":"⁷⁹"},"properties":{"noteIndex":0},"schema":""}79. The segmentation process of this tissue depot was similar to above, however a T2* threshold was not applied (in line with the assumption that there was no active BAT in this region and therefore would have a homogenous morphology) and the ROI was defined as any superficial adipose tissue existing posterior to the trapezius at the following vertebral discs: C5-C6, C6-C7 and C7-T1. Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56, Franssens et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3444","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"26620447","abstract":"The supraclavicular fat depot is known for brown adipose tissue presence. To unravel adipose tissue physiology and metabolism, high quality and reproducible imaging is required. In this study we quantified the reliability and agreement of MRI fat fraction measurements in supraclavicular and subcutaneous adipose tissue of 25 adult patients with clinically manifest cardiovascular disease. MRI fat fraction measurements were made under ambient temperature conditions using a vendor supplied mDixon chemical-shift water-fat multi-echo pulse sequence at 1.5 T field strength. Supraclavicular fat fraction reliability (intraclass correlation coefficientagreement , ICCagreement ) was 0.97 for test-retest, 0.95 for intra-observer and 0.56 for inter-observer measurements, which increased to 0.88 when ICCconsistency was estimated. Supraclavicular fat fraction agreement displayed mean differences of 0.5% (limit of agreement (LoA) -1.7 to 2.6) for test-retest, -0.5% (LoA -2.9 to 2.0) for intra-observer and 5.6% (LoA 0.4 to 10.8) for inter-observer measurements. Median fat fraction in supraclavicular adipose tissue was 82.5% (interquartile range (IQR) 78.6-84.0) and 89.7% (IQR 87.2-91.5) in subcutaneous adipose tissue (p < 0.0001). In conclusion, water-fat MRI has good reliability and agreement to measure adipose tissue fat fraction in patients with manifest cardiovascular disease. These findings enable research on determinants of fat fraction and enable longitudinal monitoring of fat fraction within adipose tissue depots. Interestingly, even in adult patients with manifest cardiovascular disease, supraclavicular adipose tissue has a lower fat fraction compared with subcutaneous adipose tissue, suggestive of distinct morphologic characteristics, such as brown adipose tissue. Copyright (c) 2015 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikendal","given":"Anouk L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR in Biomedicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"48-56","title":"Reliability and agreement of adipose tissue fat fraction measurements with water-fat MRI in patients with manifest cardiovascular disease","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁷","plainTextFormattedCitation":"57","previouslyFormattedCitation":"⁵⁷"},"properties":{"noteIndex":0},"schema":""}57, and Lundtrom et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁸","plainTextFormattedCitation":"58","previouslyFormattedCitation":"⁵⁸"},"properties":{"noteIndex":0},"schema":""}58 used a similar SAT ROI in their respective analyses, and Gifford et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶³","plainTextFormattedCitation":"63","previouslyFormattedCitation":"⁶³"},"properties":{"noteIndex":0},"schema":""}63 and Jones et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.mri.2018.04.013","ISSN":"0730725X","author":[{"dropping-particle":"","family":"Jones","given":"Terence A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wayte","given":"Sarah C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reddy","given":"Narendra L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adesanya","given":"Oludolapo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitriadis","given":"George K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barber","given":"Thomas M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutchinson","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Imaging","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"61-68","publisher":"Elsevier","title":"Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps","type":"article-journal","volume":"51"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁹","plainTextFormattedCitation":"59","previouslyFormattedCitation":"⁵⁹"},"properties":{"noteIndex":0},"schema":""}59 also used distinct thresholding approaches for BAT and SAT. A stepwise protocol for image segmentation is included in Appendix Section 7.2.5.MRI Indices of BAT ActivityQuantification of SCV BAT FF throughout the time course allows for an indication of cold-induced BAT activity. For the purposes of this study, BAT activity was quantified as: 1) Reduction in FF from baseline; 2) Magnitude of change (i.e. area under the curve (AUC); and 3) Rate of change from baseline (i.e. slope of linear regression line).Reduction in FF from BaselineReduction in SCV BAT FF and posterior neck SAT FF throughout the time course were calculated using the following formula:FF Reduction %=FF at time point x (%)-FF at time point 1 (%)Where time point 1 represented the pre-cooling FF measurement, which in turn normalized for baseline variability.Magnitude of Change in FF1742440827974001887953632899Figure SEQ Figure \* ARABIC 1 - Calculation of AUC00Figure SEQ Figure \* ARABIC 1 - Calculation of AUCAUC with the trapezoidal rule was calculated using the following equation, which can be visualized in Figure 1 below: AUC=A-B where B=Y1+Y22*(x2-x1)Rate of Change in FF2041525941355Figure SEQ Figure \* ARABIC 2 - Calculation of slope00Figure SEQ Figure \* ARABIC 2 - Calculation of slopeThe rate of change between two FF measures for a defined time interval was calculated using the “SLOPE” function in Microsoft Excel?. This function uses the following formula to derive a simple linear regression coefficient, or slope of a line between two specified time points with given y values:219773517018000Here, a negative value represented a decrease in FF, and a positive value represented an increase. AnthropometricsParticipants wore light clothing and were asked to remove shoes prior to their measurements. Weight (kg) was measured three times to the nearest 0.1kg using an electronic platform scale (BMI Scale Model 882; Seca, Hamburg, Deutschland). Height (to the nearest 0.1cm) was also obtained in triplicate using a wall-mounted stadiometer (Height Measuring Rod Model 240; Seca, Hamburg, Deutschland). The average of the three measurements were used for subsequent determination of BMI (kg/m2).Body compositionBody composition was measured using DXA (GE Lunar Prodigy Advance, Model 8743). DXA accurately assesses body composition based on the unique X-ray attenuation parameters of various tissues, such as fat and bone mineralsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"PMID":"11827768","author":[{"dropping-particle":"","family":"Genton","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hans","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kyle","given":"UG","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pichard","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nutrition","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2002"]]},"page":"66-70","title":"Dual-energy X-ray absorptiometry and body composition: differences between devices and comparison with reference methods","type":"article-journal","volume":"18"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁰","plainTextFormattedCitation":"80","previouslyFormattedCitation":"⁸⁰"},"properties":{"noteIndex":0},"schema":""}80. Total % body fat and lean mass (kg), the only measurements of interest for the present analysis, were automatically generated to the nearest 0.1% by the DXA scanner. Those with a % body fat greater than 25% were considered to have abnormal/excessive adiposityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"0683057316","author":[{"dropping-particle":"","family":"McArdle","given":"WD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katch","given":"FI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katch","given":"VL","non-dropping-particle":"","parse-names":false,"suffix":""}],"edition":"4th","id":"ITEM-1","issued":{"date-parts":[["1996"]]},"publisher":"Williams & Wilkins","publisher-place":"Baltimore","title":"Exercise physiology: nutrition, energy, and human performance","type":"book"},"uris":[""]},{"id":"ITEM-2","itemData":{"id":"ITEM-2","issued":{"date-parts":[["1995"]]},"publisher-place":"Geneva","title":"Physical Status: The use and interpretation of anthropometry. Technical Report Series 854","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"^81,82","plainTextFormattedCitation":"81,82","previouslyFormattedCitation":"^81,82"},"properties":{"noteIndex":0},"schema":""}81,82. Further, total lean mass for each participant was adjusted for their current height by calculating lean mass index (LMI = total lean mass/height2 (kg/m2)). All scans were reviewed to ensure accurate delineation of the standardized ROIs.Environmental FactorsTo ensure that ambient conditions during cooling and warming were consistent among subjects, the temperature inside the MRI scanning room (automatically displayed on the MRI control system) was recorded every 30 minutes. There were no deviations greater than ±0.5°C from the baseline-recorded temperature and therefore only the first recorded value was used for the present analysis.To determine the influence of outdoor temperature on MRI findings, the average local temperature one hour before the time course session was obtained from historical data collected by the McMaster University Weather Station (). Statistical AnalysisAnalyses were performed on Microsoft Excel?, SPSS Statistics (version 23; IBM, North Castle, NY, USA), or GraphPad Prism (version 7; GraphPad Software, La Jolla, CA, USA), and a two-tailed p-value of <0.05 denoted significance. All study variables were tested for normality using a Shapiro-Wilk W-test. Participant demographics were presented as n or n (%) for categorical variables and mean (SD) for normally distributed continuous variables or median [quartile 1 (Q1), quartile 3 (Q3)] for non-parametric data. Values were also expressed as mean (SD) in the figures. The statistical approach(es) to each objective is/are outlined below: Objective 1 – Patterns of change in SCV BAT FF during coolingThe sample size was based on a previous report by Blondin et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2013-3901","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"19457197","PMID":"24423363","abstract":"Context: Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence of its thermogenic potential and role in clearing circulating glucose and fatty acids under acute mild-cold exposure. In contrast, early indications suggest that BAT metabolism is defective in obesity and type 2 diabetes (T2D), which may have important pathological and therapeutic implications. Although, many mammalian models have demonstrated the phenotypic flexibility of this tissue through chronic cold exposure, little is known about the metabolic plasticity of BAT in humans. Objective: To determine whether four weeks of daily cold exposure could increase both the volume of metabolically active brown adipose tissue (BAT) and its oxidative capacity. Design: Six non-acclimated men were exposed to 10°C, two hours daily for four weeks (5 days/week), using a liquid-conditioned suit. Using electromyography combined with positron emission tomography with (11)C-acetate and (18)F-fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism, glucose uptake and volume prior to and following four weeks of cold acclimation were examined under controlled acute cold exposure conditions. Results: The four-week acclimation protocol elicited a 45% increase in BAT volume of activity (from 66±30 to 95±28 mL, P<0.05) and a 2.2-fold increase in cold-induced total BAT oxidative metabolism (from 0.725±0.300 to 1.591±0.326 mL·sec(-1), P<0.05). Shivering intensity was not significantly different pre- compared to post-acclimation (2.1±0.7 vs 2.0±0.5 %MVC, respectively). Fractional glucose uptake in BAT increased post-acclimation (from 0.035±0.014 to 0.048±0.012 min(-1)) while net glucose uptake trended towards an increase as well (from 163±60 to 209±50 nmol·g(-1)·min(-1)). Conclusions: These findings demonstrate that daily cold exposure not only increases the volume of metabolically active BAT, but also increases its oxidative capacity and thus its contribution to cold-induced thermogenesis.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2014"]]},"page":"438-446","title":"Increased Brown Adipose Tissue Oxidative Capacity in Cold-Acclimated Humans","type":"article-journal","volume":"99"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁹","plainTextFormattedCitation":"19","previouslyFormattedCitation":"¹⁹"},"properties":{"noteIndex":0},"schema":""}19 which showed that N=6 subjects confers a power of >80% to detect a significant cold-induced effect in BAT (at a two sided alpha level of 0.05) with the same cooling protocol and in a similar cohort of males, albeit using a different imaging modality. A time course plot of the reduction in FF from baseline allowed for a descriptive analysis of the pattern of change over time. Pairwise comparisons using a random-slope linear mixed model (LMM) with FF reduction as the dependent variable, time as the independent variable, and measures at 0 minutes (for SCV BAT and posterior neck SAT) and 180 minutes (for SCV BAT only) as the reference values, was used to identify time points of significant change in FF during the time courseADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Gueorguieva","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krystal","given":"JH","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of General Psychiatry","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2004"]]},"page":"310-317","title":"Move Over ANOVA: Progress in Analyzing Repeated-Measures Data and Its Reflection in Papers Published in the Archives of General Psychiatry","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸³","plainTextFormattedCitation":"83","previouslyFormattedCitation":"⁸³"},"properties":{"noteIndex":0},"schema":""}83,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3758/s13428-012-0281-2","ISBN":"1342801202","author":[{"dropping-particle":"","family":"Oberfeld","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franke","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Behavioural Research","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"page":"792-812","title":"Evaluating the robustness of repeated measures analyses: The case of small sample sizes and nonnormal data","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/1471-2288-12-33","ISSN":"1471-2288","author":[{"dropping-particle":"","family":"Vossoughi","given":"Mehrdad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ayatollahi","given":"S M T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towhidi","given":"Mina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ketabchi","given":"Farzaneh","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC Medical Research Methodology","id":"ITEM-2","issue":"33","issued":{"date-parts":[["2012"]]},"page":"1-10","publisher":"BioMed Central Ltd","title":"On summary measure analysis of linear trend repeated measures data: performance comparison with two competing methods","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"^84,85","plainTextFormattedCitation":"84,85","previouslyFormattedCitation":"^84,85"},"properties":{"noteIndex":0},"schema":""}84,85. This procedure was followed by Bonferroni’s multiple comparisons post hoc test. Finally, a random-intercept multilevel regression model was used to define the perceived quadratic relationship between SCV BAT FF (dependent variable) and time (independent variable).Objective 2 – Relating participant characteristics to the pattern of change in SCV BAT FFAccording to VanVoorhis et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.20982/tqmp.03.2.p043","ISBN":"1913-4126","ISSN":"1913-4126","abstract":"This article addresses the definition of power and its relationship to Type I and Type II errors. We discuss the relationship of sample size and power. Finally, we offer statistical rules of thumb guiding the selection of sample sizes large enough for sufficient power to detecting differences, associations, chi‐square, and factor analyses.","author":[{"dropping-particle":"","family":"Wilson VanVoorhis","given":"Carmen R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morgan","given":"Betsy L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Tutorials in Quantitative Methods for Psychology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2007"]]},"note":"From Duplicate 1 (Understanding Power and Rules of Thumb for Determining Sample Sizes - Wilson Betsy L, Carmen R.; Morgan)\n\nNULL","page":"43-50","title":"Understanding Power and Rules of Thumb for Determining Sample Sizes","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁶","plainTextFormattedCitation":"86","previouslyFormattedCitation":"⁸⁶"},"properties":{"noteIndex":0},"schema":""}86, a sample size of no less than 50 subjects is required to make a definitive conclusion regarding the relationship between two variables; therefore, this analysis was underpowered. Nevertheless, a Spearman rank-order correlation was performed to assess the association between indices of body composition (i.e. BMI and % total body fat) and indices of BAT activity (i.e. AUC and FF reduction) at time points of interest as identified in objective 1.Objective 3 - Patterns of change in SCV BAT FF during warmingThe rationale used for determining an appropriate sample size to accomplish objective 1 was also applied to objective 3. Further, a descriptive analysis of the time course of change in FF from baseline was the only statistical approach used to accomplish this objective.RESULTSProject Recruitment-120652490812Figure SEQ Figure \* ARABIC 3 - Recruitment Flow Chart for the GETBAT Timecourse Substudy00Figure SEQ Figure \* ARABIC 3 - Recruitment Flow Chart for the GETBAT Timecourse Substudy-1968596549300Between the months of June 2017 and February 2018, a total of 40 males under the age of 30 expressed interest in the study, and 12 were eventually enrolled (30% enrollment rate). The recruitment flow chart is presented in Figure 3 below.Participant CharacteristicsThe mean±SD of BMI, LMI, and % total body fat were 24.7±2.8kg/m2, 17.6±1.6kg/m2 and 25.0±7.4%, respectively. Of the six participants with an “overweight” BMI (≥25.0kg/m2), four had excess adiposity (>25%), and of the six subjects with a non-overweight BMI (<25.0 kg/m2), one had excess adiposityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISBN":"0683057316","author":[{"dropping-particle":"","family":"McArdle","given":"WD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katch","given":"FI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katch","given":"VL","non-dropping-particle":"","parse-names":false,"suffix":""}],"edition":"4th","id":"ITEM-1","issued":{"date-parts":[["1996"]]},"publisher":"Williams & Wilkins","publisher-place":"Baltimore","title":"Exercise physiology: nutrition, energy, and human performance","type":"book"},"uris":[""]},{"id":"ITEM-2","itemData":{"id":"ITEM-2","issued":{"date-parts":[["1995"]]},"publisher-place":"Geneva","title":"Physical Status: The use and interpretation of anthropometry. Technical Report Series 854","type":"report"},"uris":[""]}],"mendeley":{"formattedCitation":"^81,82","plainTextFormattedCitation":"81,82","previouslyFormattedCitation":"^81,82"},"properties":{"noteIndex":0},"schema":""}81,82. During the time course cold exposure session, 7 (58.3%) participants endured the full three hours of cold exposure, whereas the remaining 5 (41.7%) lasted at least one hour. Given the narrow dispersion of values for air temperature inside the MRI room (min,max = 19.2,21.0°C) and ΔOutlet-Inlet (min,max = 3.37,3.67°C), the intensity of cooling and resultant whole-body thermogenic response were comparable across the cohort (Table 2 below).Table SEQ Table \* ARABIC 2 – Variable Descriptives for the GETBAT Timecourse SubstudyVARIABLEN (%)MEAN (SD) OR MEDIAN [Q1,Q3)MIN,MAXPARTICIPANT CHARACTERISTICSAge (years)1222.8 (2.6)19,28BMI (kg/m2)1224.7 (2.8)19.8,28.9Normal6 (50)22.4 (1.7)19.8,24.4Overweight6 (50)27.1 (1.2)25.5,28.9LMI (kg/m2)1217.6 (1.6)14.7,20.0% Total Fat1225.0 (7.4)15.6,38.4≤25%7 (58.3)19.8 (2.7)15.6,22.2>25%5 (41.7)32.3 (5.3)26.0,38.4TIME COURSE MRI SESSIONAmbient Temperature (°C)10*20.3 (0.5)19.2,21.0Inlet Temperature (°C)6?18.88 (0.17)18.60,19.03ΔOutlet-Inlet (°C)6?3.49 (0.11)3.37,3.67Duration of Cold Exposure12180 [82.5,180]60,180=60 minutes3 (25)-->60 but <180 minutes2 (16.7)--180 minutes7 (58.3)--Outdoor Temperature (°C)122.9 (10.9)(-12.2,18.9)Month of Visit12--June/July2 (16.7)--Oct/Nov4 (33.3)--Dec/Jan/Feb6 (50)--?Data for 6 participants lost due to technical difficulties*Temperature of the MRI room was not recorded for the first two participantsValues are means (SD) for normally distributed data and median [Q1,Q3] for non-parametric dataData collection and analysis summaryTable SEQ Table \* ARABIC 3 - MRI Acquisition and Analysis SummaryCOOLINGWARMINGTIME POINTSCANS COLLECTEDSCANS ANALYZEDTIME POINTSCANS COLLECTEDSCANS ANALYZED012125111151211101111101212151110151212201110201111251110251110301111301212351010401094512125010105510960121175999099105881208813588150771657718077The number of scans acquired and analyzed are shown in Table 3. Twelve scans were not collected at each time point due to change of protocol after the first two subjects and differential ability to withstand the cold challenge. In total, five scans collected during cooling of the participants could not be analyzed due to excessive motion artifacts that made delineation of anatomical borders impossible (n=3), or a technical limitation in post-image processing termed fat-water swapping (n=2)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61. One of the twelve subjects did not proceed with warming, and a further three scans were lost due to fat-water swappingADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61.Identifying the time course of change in SCV BAT FF with coolingThe first objective of this project was to identify the pattern of change in SCV BAT FF during 3-hour cold exposure at 18°C. All participants exhibited a measurable decrease in FF regardless of the duration of cooling. In fact, the nadir FF was detected before the end of cooling in all but one participant (Subject 10 in Table 4). Individual time course plots can be found in Appendix Section 7.3.1.Table SEQ Table \* ARABIC 4 - Summary of individual cold-induced changes in SCV BAT FFSUBJECTPRE-COLD FF (%)MAX FF REDUCTION (%)TIME TO MAX FF REDUCTION (min)FF REDUCTION @ END OF COLD (%)DURATION OF COLD (min)174.694.691051.80180271.732.89600.65180374.524.031503.34180475.606.14506.0760574.152.11200.3060667.756.971053.06135770.905.421354.02180868.867.43457.1660962.226.441503.191801059.354.34904.34901163.787.711355.901801266.858.511356.48180The cold-induced reduction in FF was immediate and increased in magnitude over the first 90 minutes, after which values were largely maintained until the end of cooling (Figure 4A,B). Further, the mean slope (i.e. rate of change in SCV BAT FF) throughout the time course appeared to shift from being predominantly negative (i.e. declining FF) to a period of variability around the x-axis (i.e. little change in FF) at roughly 90 minutes (Figure 4C). These observations were maintained when those who did not complete the full duration of cold exposure were removed from the analysis (n=7, see Figure 16 in Appendix Section 7.3.4). Overall, these findings suggested that there was little change in FF beyond the 90 minutes of cold exposure.32902985276850Figure SEQ Figure \* ARABIC 4 – Changes in SCV BAT FF during cooling. Time course plots of FF reduction (A), AUC for 30 minute intervals (B), and slope for 30 minute intervals (C). Data are presented as mean±SD.00Figure SEQ Figure \* ARABIC 4 – Changes in SCV BAT FF during cooling. Time course plots of FF reduction (A), AUC for 30 minute intervals (B), and slope for 30 minute intervals (C). Data are presented as mean±SD.-172085199961500As an exploratory outcome of the present study, SCV BAT T2* was measured concomitantly with FF. Depicted in Figure 15 in Appendix Section 7.3.3, T2* showed an immediate cold-induced decrease (i.e. a greater amount of DeoxyHb relative to OxyHb as a consequence of oxygen consumption in the BAT tissue) which was sustained throughout the duration of cooling. Considering FF and T2* together, it can be postulated SCV BAT responds immediately to a cold challenge by liberating and oxidizing substrate, resulting in the production of heat.Identifying Time Points of InterestGiven that cold-induced changes in SCV BAT FF appeared to be rapid and transient, we were interested in determining the earliest point at which a significant reduction from baseline had occurred. Further, we were curious as to whether or not there became a point during the time course at which changes no longer differed from those measured after 3 hours of cooling (the usual post-cold time point). A significant reduction in FF was detected as soon as 10 minutes following the onset of cold exposure (mean difference = -1.60%; p=0.007). This analysis was repeated with “180 minutes” used as the reference value and it was found that beyond 35 minutes, reductions in FF no longer differed from those measured at the end of the cooling protocol (p>0.05). Tabular output from this analysis can be found in Appendix Section 7.3.5.Modeling the change in FF over timeIt was also of interest to mathematically describe the relationship between FF (dependent variable) and time (dependent variable) using a random-effects multilevel regression model. Relevant parameters and a visual representation of the model are included in Table 5 and Figure 5 below, respectively:Table SEQ Table \* ARABIC 5 - Random-effects multilevel regression model describing the relationship between FF (dependent variable) and time (independent variable)PARAMTERESTIMATESTD. ERRORP-VALUE95% CI LL95% CI ULIntercept68.501.62<0.001*65.3371.66Time-0.0540.0058<0.001*-0.065-0.042Time20.000190.000033<0.001*0.000130.00026rho0.960.017<0.001*0.910.98Overall model:FF% at a specified time point=68.50-0.054time+0.00019time2+εCI = confidence interval; LL = lower limit; UL = upper limitThe coefficients (i.e. slopes) for time (linear parameter; β=-0.054) and time2 (quadratic parameter; β=0.00019) were statistically significantly different from 0 (p <0.001 for all), indicating that each had a meaningful impact on FF%. Further, a significant rho (or intraclass correlation (ICC)) value of 0.96 suggests that 96% of the variance in FF% was explained by accounting for individual variation (i.e. random intercepts, where each subject is a distinct cluster) in the model. Since the exposure conditions were kept constant across all subjects (e.g. overnight fast, time of day, acclimation period, and cooling intensity), much of the observed variability in response can in turn be linked to an individual’s innate ability to generate heat, which is dependent on the following equation: Hprod = shivering thermogenesis (ST) + NST. Factors that could potentially implicate the latter variable within this equation (i.e. NST) were explored in the subsequent section. In general, the model was considered to be of good fit based on the highly significant p-values corresponding to all parameters which described the relationship between FF and time.659765173482000Finally, deriving an equation to predict the SCV BAT FF at a given time point increases the generalizability of the results of this study. In an analogous population of males who underwent a cold challenge that was similar in intensity but varied in duration, SCV BAT FF findings of past and future studies can be compared. Though preliminary, this is a novel attempt at using a model to predict one’s BAT-specific response to a cold challenge.11715753376393Figure SEQ Figure \* ARABIC 5 - Graphical representation of the quadratic model (red) for the absolute change in SCV BAT FF (black)00Figure SEQ Figure \* ARABIC 5 - Graphical representation of the quadratic model (red) for the absolute change in SCV BAT FF (black)The time course of change of posterior neck SAT FF-10160024187150033229555532755Figure SEQ Figure \* ARABIC 6 – Changes posterior neck SAT FF during cooling. Time course plots of FF reduction (A), AUC for 30-minute intervals (B), and slope for 30 minute intervals (C). Data are presented as mean±SD.00Figure SEQ Figure \* ARABIC 6 – Changes posterior neck SAT FF during cooling. Time course plots of FF reduction (A), AUC for 30-minute intervals (B), and slope for 30 minute intervals (C). Data are presented as mean±SD.Measurements of the posterior neck SAT were obtained in parallel with the SCV BAT. Visually, the FF of this adipose tissue depot did not considerably change throughout the time course (Figure 6A-C). Although mean values were consistently below reference time point 0, suggesting that the posterior neck SAT was metabolically active during cooling and in turn opposing my a priori hypothesis, these changes were not statistically significant (Tables 15 and 16 in Appendix Section 7.3.6). Furthermore, in some subjects, the pattern of change in posterior neck SAT mirrored that of the SCV BAT (Appendix Section 7.3.1), which might also allude to the unique thermogenic properties of this tissue depot. Investigating if participant characteristics are related to the pattern of cold-induced change2159016122650031413452334553Figure SEQ Figure \* ARABIC 7 - Individual patterns of FF reduction among those who completed the full cooling protocol (n=7)00Figure SEQ Figure \* ARABIC 7 - Individual patterns of FF reduction among those who completed the full cooling protocol (n=7)Since not all participants withstood the entire duration of cooling, covariates of BAT activity were compared between those who completed the full cold exposure and those who did not. In brief, no discernible group-specific patterns for temperature (i.e. outdoor and ambient)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]},{"id":"ITEM-3","itemData":{"ISSN":"01615505","author":[{"dropping-particle":"","family":"Cohade","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mourtzikos","given":"Karen A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-3","issued":{"date-parts":[["2003"]]},"page":"1267-1271","title":"“ USA-Fat ”: Prevalence Is Related to Ambient Outdoor Temperature — Evaluation with 18 F-FDG PET/CT","type":"article-journal","volume":"44"},"uris":[""]}],"mendeley":{"formattedCitation":"^30,31,41","plainTextFormattedCitation":"30,31,41","previouslyFormattedCitation":"^30,31,41"},"properties":{"noteIndex":0},"schema":""}30,31,41 or indices of body composition (i.e. BMI, LMI, and % body fat)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1056/NEJMoa0810780","ISBN":"1533-4406 (Electronic)\\n0028-4793 (Linking)","ISSN":"0028-4793","PMID":"19357406","abstract":"Background Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. Methods We analyzed 3640 consecutive 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomographic and computed tomographic (PET–CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of 18F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from t...","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lehman","given":"Sanaz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Williams","given":"Gethin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodman","given":"Dean","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goldfine","given":"Allison B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuo","given":"Frank C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Edwin L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-Hua","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doria","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C. Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"New England Journal of Medicine","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2009","4"]]},"page":"1509-1517","title":"Identification and Importance of Brown Adipose Tissue in Adult Humans","type":"article-journal","volume":"360"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db09-0530","ISBN":"1939-327X (Electronic)\\r0012-1797 (Linking)","ISSN":"00121797","PMID":"19401428","abstract":"OBJECTIVE The significant roles of brown adipose tissue (BAT) in the regulation of energy expenditure and adiposity are established in small rodents but have been controversial in humans. The objective is to examine the prevalence of metabolically active BAT in healthy adult humans and to clarify the effects of cold exposure and adiposity. RESEARCH DESIGN AND METHODS In vivo 2-[(18)F]fluoro-2-deoxyglucose (FDG) uptake into adipose tissue was measured in 56 healthy volunteers (31 male and 25 female subjects) aged 23-65 years by positron emission tomography (PET) combined with X-ray computed tomography (CT). RESULTS When exposed to cold (19 degrees C) for 2 h, 17 of 32 younger subjects (aged 23-35 years) and 2 of 24 elderly subjects (aged 38-65 years) showed a substantial FDG uptake into adipose tissue of the supraclavicular and paraspinal regions, whereas they showed no detectable uptake when kept warm (27 degrees C). Histological examinations confirmed the presence of brown adipocytes in these regions. The cold-activated FDG uptake was increased in winter compared with summer (P < 0.001) and was inversely related to BMI (P < 0.001) and total (P < 0.01) and visceral (P < 0.001) fat areas estimated from CT image at the umbilical level. CONCLUSIONS Our findings, being against the conventional view, indicate the high incidence of metabolically active BAT in adult humans and suggest a role in the control of body temperature and adiposity.","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Watanabe","given":"Kumiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nio-Kobayashi","given":"Junko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nakada","given":"Kunihiro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2009","7"]]},"page":"1526-1531","title":"High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1152/ajpendo.00298.2010.","ISBN":"1522-1555 (Electronic)\\r0193-1849 (Linking)","ISSN":"0193-1849","PMID":"20606075","abstract":"Brown adipose tissue (BAT) plays a major role in energy homeostasis in animals. Detection of BAT using positron emission tomography (PET)-CT in humans has challenged the view that BAT disappears after infancy. Several recent studies, based on analysis of single scans, have reported a low prevalence of only 5-10% in humans, casting doubt on its significance. We undertook a critical analysis of the sensitivity, reproducibility, and accuracy of PET-CT to deduce the prevalence of BAT and factors associated with its detection in adult humans. In a retrospective evaluation of PET-CT, using [18F]fluorodeoxyglucose, performed in 2,934 patients, BAT was identified in 250 patients, yielding an apparent prevalence of 8.5%. Among those patients with BAT, 145 were scanned more than once. The frequency of another scan being positive increased from 8 to 65% for one to more than four additional studies. The average probability of obtaining another positive scan among patients with BAT is 13%, from which the prevalence of BAT is estimated at 64%. BAT was more commonly detected in women, in younger (36 ± 1 vs. 52 ± 1 years, P < 0.001) and leaner (20.1 ± 0.9 vs. 24.9 ± 0.9 kg/m2, P < 0.01) individuals. Fasting glucose was lower in those with BAT than those without (4.9 ± 0.1 vs. 5.5 ± 0.1 mmol/l, P < 0.01). Among patients scanned more than once, BAT was detected when body weight and fasting glucose were lower (54.9 ± 0.5 vs. 58.2 ± 0.8 kg, P < 0.001 and 4.9 ± 0.3 vs. 5.5 ± 0.3 mmol/l, P = 0.03). We conclude that BAT is present in the majority of adult humans. Presence of BAT correlates negatively with body mass index and glucose concentration. BAT may play an important role in energy homeostasis in adults.","author":[{"dropping-particle":"","family":"Lee","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Greenfield","given":"Jerry R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ho","given":"Ken K Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fulham","given":"Michael J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Endocrinology and Metabolism","id":"ITEM-4","issue":"4","issued":{"date-parts":[["2010","10"]]},"page":"601-606","title":"A critical appraisal of the prevalence and metabolic significance of brown adipose tissue in adult humans","type":"article-journal","volume":"299"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1038/jcbfm.2014.50","ISSN":"0271-678X","author":[{"dropping-particle":"","family":"Orava","given":"Janne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nummenmaa","given":"Lauri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noponen","given":"Tommi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viljanen","given":"Tapio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Cerebral Blood Flow & Metabolism","id":"ITEM-5","issue":"6","issued":{"date-parts":[["2014"]]},"page":"1018-1023","publisher":"Nature Publishing Group","title":"Brown adipose tissue function is accompanied by cerebral activation in lean but not in obese humans","type":"article-journal","volume":"34"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1007/s00247-015-3391-z","ISSN":"14321998","abstract":"Brown adipose tissue (BAT) is identified in mammals as an adaptive thermogenic organ for modulation of energy expenditure and heat generation. Human BAT may be primarily composed of brown-in-white (BRITE) adipocytes and stimulation of BRITE may serve as a potential target for obesity interventions. Current imaging studies of BAT detection and characterization have been mainly limited to PET/CT. MRI is an emerging application for BAT characterization in healthy children.\\r\\nTo exploit Dixon and diffusion-weighted MRI methods to characterize cervical-supraclavicular BAT/BRITE properties in normal-weight and obese children while accounting for pubertal status.\\r\\nTwenty-eight healthy children (9-15 years old) with a normal or obese body mass index participated. MRI exams were performed to characterize supraclavicular adipose tissues by measuring tissue fat percentage, T2*, tissue water mobility, and microvasculature properties. We used multivariate linear regression models to compare tissue properties between normal-weight and obese groups while accounting for pubertal status.\\r\\nMRI measurements of BAT/BRITE tissues in obese children showed higher fat percentage (P < 0.0001), higher T2* (P < 0.0001), and lower diffusion coefficient (P = 0.015) compared with normal-weight children. Pubertal status was a significant covariate for the T2* measurement, with higher T2* (P = 0.0087) in pubertal children compared to prepubertal children. Perfusion measurements varied by pubertal status. Compared to normal-weight children, obese prepubertal children had lower perfusion fraction (P = 0.003) and pseudo-perfusion coefficient (P = 0.048); however, obese pubertal children had higher perfusion fraction (P = 0.02) and pseudo-perfusion coefficient (P = 0.028).\\r\\nThis study utilized chemical-shift Dixon MRI and diffusion-weighted MRI methods to characterize supraclavicular BAT/BRITE tissue properties. The multi-parametric evaluation revealed evidence of morphological differences in brown adipose tissues between obese and normal-weight children.","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoeneman","given":"Samantha E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Huiyuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwon","given":"Soyang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rigsby","given":"Cynthia K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Josefson","given":"Jami L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-6","issue":"11","issued":{"date-parts":[["2015"]]},"page":"1682-1689","title":"MRI characterization of brown adipose tissue in obese and normal-weight children","type":"article-journal","volume":"45"},"uris":[""]}],"mendeley":{"formattedCitation":"^{29–31,36,87,88}","plainTextFormattedCitation":"29–31,36,87,88","previouslyFormattedCitation":"^{29–31,36,87,88}"},"properties":{"noteIndex":0},"schema":""}29–31,36,87,88 were present. A summary of these findings are included in Appendix Section 7.3.7.As evidenced by Figure 7 above, there was notable variability in the patterns of change in SCV BAT FF among those who sustained the full 180 minutes of cold exposure. Therefore, we were interested in exploring the relationships between expected covariates of BAT activity (based on the literature) and an individual’s BAT-specific response to cold exposure. Given the abundance of evidence suggesting an association between BMI and % body fat and BAT activityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI67803DS1","author":[{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aita","given":"Sayuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kayahara","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Investgation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2013"]]},"page":"3404-3408","title":"Recruited brown adipose tissue as an antiobesity agent in humans","type":"article-journal","volume":"123"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2015.09.007","ISBN":"1932-7420 (Electronic)\r1550-4131 (Linking)","ISSN":"19327420","PMID":"26445512","abstract":"Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.","author":[{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2015"]]},"page":"546-559","publisher":"Elsevier Inc.","title":"Brown and beige fat: Physiological roles beyond heat generation","type":"article-journal","volume":"22"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2012-1289","author":[{"dropping-particle":"","family":"Vijgen","given":"G H E 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Journal of Obesity","id":"ITEM-5","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"doi:10.2967/jnumed.112.111336.","ISBN":"1535-5667 (Electronic)\\n0161-5505 (Linking)","ISSN":"1535-5667","PMID":"23362317","abstract":"UNLABELLED Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. METHODS Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. RESULTS The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40…","author":[{"dropping-particle":"","family":"Muzik","given":"Otto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangner","given":"Thomas J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"William R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Ajay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janisse","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-6","issue":"4","issued":{"date-parts":[["2013","4"]]},"note":"From Duplicate 2 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, Otto; Mangner, Thomas J; Leonard, William R; Kumar, Ajay; Janisse, James; Granneman, James G)\n\nFrom Duplicate 1 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, O; Manger, T; Leonard, WR; Kumar, A; Janisse, J; Granneman, JG)\n\nNULL","page":"523-531","publisher":"Society of Nuclear Medicine","title":"15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat","type":"article-journal","volume":"54"},"uris":[""]},{"id":"ITEM-7","itemData":{"DOI":"10.1038/s41598-017-16463-6","author":[{"dropping-particle":"","family":"Alcalá","given":"Martín","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calderon-Dominguez","given":"María","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bustos","given":"Eduviges","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"Pilar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casals","given":"Núria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serra","given":"Dolors","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viana","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrero","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-7","issue":"8","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"Increased inflammation , oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-8","itemData":{"DOI":"10.1194/jlr.M079665","author":[{"dropping-particle":"","family":"Kotzbeck","given":"Petra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giordano","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mondini","given":"Eleonora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murano","given":"Incoronata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Severi","given":"Ilenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Venema","given":"Wiebe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cecchini","given":"Maria Paola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cinti","given":"Saverio","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-8","issue":"3","issued":{"date-parts":[["2018"]]},"page":"1-37","title":"Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^{12,38,73,89–93}","plainTextFormattedCitation":"12,38,73,89–93","previouslyFormattedCitation":"^{12,38,73,89–93}"},"properties":{"noteIndex":0},"schema":""}12,38,73,89–93, these indices of body composition were correlated with indices of BAT activity (i.e. FF reduction from baseline and AUC from baseline, the latter of which accounts for all measurements within a time interval of interest) at 10 minutes (i.e. the earliest point at which significant changes occurred); 60 minutes (i.e. the first hour of cold exposure); 90 minutes (i.e. the point at which FF appeared to reach a nadir), and 180 minutes (i.e. end of exposure).BMI and % total body fat were at least moderately related to indices of BAT activity at all time points of interest (Figure 8A; corresponding p-values are included in Table 18 in Appendix Section 7.3.7). In fact, a strong negative correlation between BMI and AUC existed as soon as 10 minutes following the onset of cold (rho=-0.786), indicating that those with a lower BMI had a larger magnitude 1397007721600Figure SEQ Figure \* ARABIC 8 – Correlation matrix identifying the Spearman’s rho value for each combination of BMI and % body fat and indicator of BAT activity at 10 minutes, 60 minutes, 90 minutes, and 180 minutes (A). Time course of FF reduction according to BMI and % fat classifications (B). *denotes statistical significance at p<0.05. N=7 in each analysis.00Figure SEQ Figure \* ARABIC 8 – Correlation matrix identifying the Spearman’s rho value for each combination of BMI and % body fat and indicator of BAT activity at 10 minutes, 60 minutes, 90 minutes, and 180 minutes (A). Time course of FF reduction according to BMI and % fat classifications (B). *denotes statistical significance at p<0.05. N=7 in each analysis.53340067310000of change in FF at this point. These relationships were also visually apparent according to Figure 8B. As an exploratory analysis, a plot of the strength of these correlations at each cold-induced time point was constructed (see Figure 20 in Appendix Section 7.3.7). Unlike FF reduction, the associations between AUC and indices of body composition appeared to follow a discernible time-dependent pattern until 75 minutes, after which rho values remained consistent until the end of the cold challenge. Not only does this finding corroborate the time course of change in SCV BAT FF, it also suggests that AUC might be a more robust indicator of BAT activity than FF reduction. Identifying the time course of change in SCV BAT FF with warming125349097374800The final objective of this thesis was to identify the time course of change in SCV BAT FF during a period of warming at 32°C for 30 minutes. In performing this phase immediately following cooling, the effect of BAT “deactivation” could be quantified. 13007652353310Figure SEQ Figure \* ARABIC 9 - Time course of FF reduction during warming in the SCV BAT. Data are mean±SD.00Figure SEQ Figure \* ARABIC 9 - Time course of FF reduction during warming in the SCV BAT. Data are mean±SD.The pre-cold FF measurement was used as the reference value, and therefore Figure 9 represents FF reduction relative to that point. It was hypothesized that warming would induce a recovery of FF towards baseline (i.e. the x-axis) since the sympathetic stimulus, and hence the driver of BAT-specific NST, would be absent. However, neither the pattern nor the magnitude of change in FF was influenced by a whole-body exposure to warming, as FF appeared to be maintained at or around the last measured cold-induced value. Whether or not this phenomenon was due to a lack of substrate to replenish intracellular TAG stores, or a concomitant increase in perfusion and lipid droplet anabolism, is uncertainADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0077907","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"24205024","abstract":"There is a major resurgence of interest in brown adipose tissue (BAT) biology, particularly regarding its determinants and consequences in newborns and infants. Reliable methods for non-invasive BAT measurement in human infants have yet to be demonstrated. The current study first validates methods for quantitative BAT imaging of rodents post mortem followed by BAT excision and re-imaging of excised tissues. Identical methods are then employed in a cohort of in vivo infants to establish the reliability of these measures and provide normative statistics for BAT depot volume and fat fraction. Using multi-echo water-fat MRI, fat- and water-based images of rodents and neonates were acquired and ratios of fat to the combined signal from fat and water (fat signal fraction) were calculated. Neonatal scans (n = 22) were acquired during natural sleep to quantify BAT and WAT deposits for depot volume and fat fraction. Acquisition repeatability was assessed based on multiple scans from the same neonate. Intra- and inter-rater measures of reliability in regional BAT depot volume and fat fraction quantification were determined based on multiple segmentations by two raters. Rodent BAT was characterized as having significantly higher water content than WAT in both in situ as well as ex vivo imaging assessments. Human neonate deposits indicative of bilateral BAT in spinal, supraclavicular and axillary regions were observed. Pairwise, WAT fat fraction was significantly greater than BAT fat fraction throughout the sample (ΔWAT-BAT = 38 %, p<10(-4)). Repeated scans demonstrated a high voxelwise correlation for fat fraction (Rall = 0.99). BAT depot volume and fat fraction measurements showed high intra-rater (ICCBAT,VOL = 0.93, ICCBAT,FF = 0.93) and inter-rater reliability (ICCBAT,VOL = 0.86, ICCBAT,FF = 0.93). This study demonstrates the reliability of using multi-echo water-fat MRI in human neonates for quantification throughout the torso of BAT depot volume and fat fraction measurements.","author":[{"dropping-particle":"","family":"Rasmussen","given":"Jerod M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Entringer","given":"Sonja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nguyen","given":"Annie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erp","given":"Theo G M","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guijarro","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oveisi","given":"Fariba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swanson","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piomelli","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wadhwa","given":"Pathik D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buss","given":"Claudia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potkin","given":"Steven G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"title":"Brown adipose tissue quantification in human neonates using water-fat separated MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"^56,69","plainTextFormattedCitation":"56,69","previouslyFormattedCitation":"^56,69"},"properties":{"noteIndex":0},"schema":""}56,69. To offer insight into the latter notion, changes in T2* were recorded and a similar effect was seen in that this measurement was not influenced by 30 minutes of warming at 32°C (see Figure 21 in Appendix Section 7.3.8). DISCUSSIONThe first objective of this project was to identify the patterns of change in SCV BAT FF during a 3-hour mild cold exposure. Second, we were interested in seeing if expected covariates of BAT activity were related to indices of BAT activity at various points throughout the time course. Finally, we wanted to measure the trajectory of SCV BAT FF during a transition from cooling to 30 minutes of warming (i.e. BAT “deactivation”). The results of these three objectives will be discussed in sequence below.Objective 1: Time Course of Change in SCV BAT FF over cooling Pre- and post- cold measurements of SCV BAT FFThe distribution of pre-cold SCV BAT FF values (range: 59.35%-75.60%) within this small sample of male adults was comparable to what has been reported for similar populations ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^38,63","plainTextFormattedCitation":"38,63","previouslyFormattedCitation":"^38,63"},"properties":{"noteIndex":0},"schema":""}38,63. In particular, Gifford et al. (2016) identified a slightly wider interval of 51.6-78.7% in a cohort of 17 normal and overweight subjects (11 females and 6 males) under the age of 30 using a combined MRI and PET/CT thresholding approach (CT radiodensity between -200 and -2 HU, MRI FF between 50-100%, MRI R2* <150 s-1 (T2* >7 msec), and no limits on FDG uptake) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶³","plainTextFormattedCitation":"63","previouslyFormattedCitation":"⁶³"},"properties":{"noteIndex":0},"schema":""}63. Deng et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 studied 11 normal and overweight males under the age of 30 and used a stepwise SCV BAT segmentation algorithm (subject-specific R2* and FF thresholding values) to report a mean (standard deviation) of 70% (8%) under non-cold stimulated conditions. The notable differences in ROI selection procedures between the present study and those conducted previously likely contribute to the slight variability in findings.Further, all subjects, regardless of the duration of cooling, had a measurable reduction in FF (Table 4). Among the seven males who completed the full 180 minutes, the mean reduction in FF from baseline was 3.62% (range: 0.65%-6.48%). This finding is comparable to Ong et al. (unpublished), who utilized the same cold exposure protocol and reported a mean FF decrease of 2.97% in a cohort of males and females between the ages of 18 and 50. To date, no published study has combined a standardized, whole-body cold exposure using a water-perfused suit with MRI-derived FF measurements. Of those who have reported a mean change in FF during cooling, the magnitude of response was variable (range: 0.4%-5.0%)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.metabol.2017.02.001","ISSN":"00260495","PMID":"28403942","author":[{"dropping-particle":"","family":"Holstila","given":"Milja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pesola","given":"Marko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"Ronald J.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"23-30","publisher":"Elsevier Inc.","title":"MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure","type":"article-journal","volume":"70"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.metabol.2016.03.012","ISBN":"1532-8600 (Electronic) 0026-0495 (Linking)","ISSN":"15328600","PMID":"27173471","abstract":"Objective. To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze. Design Randomized, open, parallel-group trial. Methods. Healthy non-selected participants were randomized to achieve cold-exposure 1 hour/day, or to avoid any sense of feeling cold, for 6 weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI). Results. Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841 ?? 199 kCal/24 h to 1795 ?? 213 kCal/24 h, p = 0.047 cold-activated MR from 1900 ?? 150 kCal/24 h to 1793 ?? 215 kCal/24 h, p = 0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p = 0.052). The difference between MR changes by the interventions between groups was statistically significant (p = 0.008 at room temperature, p = 0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported ??? 8 days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175 ?? 0.015 l to 0.0216 ?? 0.014 l, p = 0.049). Conclusions. We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans.","author":[{"dropping-particle":"","family":"Romu","given":"Thobias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vavruch","given":"Camilla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dahlqvist-Leinhard","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tallberg","given":"Joakim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dahlstr??m","given":"Nils","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Persson","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heglind","given":"Mikael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lidell","given":"Martin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enerb??ck","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borga","given":"Magnus","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nystrom","given":"Fredrik H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism: Clinical and Experimental","id":"ITEM-2","issue":"6","issued":{"date-parts":[["2016"]]},"page":"926-934","publisher":"The Authors","title":"A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans","type":"article-journal","volume":"65"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-3","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-4","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1111/dom.12433","ISBN":"1463-1326 (Electronic) 1462-8902 (Linking)","ISSN":"14631326","PMID":"25586670","abstract":"The aim of the present study was to determine whether single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) can non-invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using (18)F-fluorodeoxyglucose positron emission tomography (PET) and (15)O-H2O PET perfusion during cold exposure, and (1)H-MRS at ambient temperature. Image-guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by (1)H-MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8-year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M-value; euglycaemic-hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76-95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by (1)H-MRS may be an independent marker of whole-body insulin sensitivity, independent of brown adipose tissue metabolic activation.","author":[{"dropping-particle":"","family":"Raiko","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holstila","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"K. A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Orava","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Niemi","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laine","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Taittonen","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"R. J H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes, Obesity and Metabolism","id":"ITEM-5","issue":"5","issued":{"date-parts":[["2015"]]},"page":"516-519","title":"Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity","type":"article-journal","volume":"17"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-6","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]},{"id":"ITEM-7","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-7","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-8","itemData":{"DOI":"10.1007/s00247-015-3391-z","ISSN":"14321998","abstract":"Brown adipose tissue (BAT) is identified in mammals as an adaptive thermogenic organ for modulation of energy expenditure and heat generation. Human BAT may be primarily composed of brown-in-white (BRITE) adipocytes and stimulation of BRITE may serve as a potential target for obesity interventions. Current imaging studies of BAT detection and characterization have been mainly limited to PET/CT. MRI is an emerging application for BAT characterization in healthy children.\\r\\nTo exploit Dixon and diffusion-weighted MRI methods to characterize cervical-supraclavicular BAT/BRITE properties in normal-weight and obese children while accounting for pubertal status.\\r\\nTwenty-eight healthy children (9-15 years old) with a normal or obese body mass index participated. MRI exams were performed to characterize supraclavicular adipose tissues by measuring tissue fat percentage, T2*, tissue water mobility, and microvasculature properties. We used multivariate linear regression models to compare tissue properties between normal-weight and obese groups while accounting for pubertal status.\\r\\nMRI measurements of BAT/BRITE tissues in obese children showed higher fat percentage (P < 0.0001), higher T2* (P < 0.0001), and lower diffusion coefficient (P = 0.015) compared with normal-weight children. Pubertal status was a significant covariate for the T2* measurement, with higher T2* (P = 0.0087) in pubertal children compared to prepubertal children. Perfusion measurements varied by pubertal status. Compared to normal-weight children, obese prepubertal children had lower perfusion fraction (P = 0.003) and pseudo-perfusion coefficient (P = 0.048); however, obese pubertal children had higher perfusion fraction (P = 0.02) and pseudo-perfusion coefficient (P = 0.028).\\r\\nThis study utilized chemical-shift Dixon MRI and diffusion-weighted MRI methods to characterize supraclavicular BAT/BRITE tissue properties. The multi-parametric evaluation revealed evidence of morphological differences in brown adipose tissues between obese and normal-weight children.","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoeneman","given":"Samantha E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Huiyuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwon","given":"Soyang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rigsby","given":"Cynthia K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Josefson","given":"Jami L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-8","issue":"11","issued":{"date-parts":[["2015"]]},"page":"1682-1689","title":"MRI characterization of brown adipose tissue in obese and normal-weight children","type":"article-journal","volume":"45"},"uris":[""]}],"mendeley":{"formattedCitation":"^{56,58,63,70–72,74,88}","plainTextFormattedCitation":"56,58,63,70–72,74,88","previouslyFormattedCitation":"^{56,58,63,70–72,74,88}"},"properties":{"noteIndex":0},"schema":""}56,58,63,70–72,74,88.Pattern of change in SCV BAT FF during coolingIn this study, a standardized, whole-body cold exposure protocol was used and acquisition of SCV BAT FF measurements at frequent, predefined intervals in healthy young men was carried out. We concluded that cold-induced changes in SCV BAT FF were immediate and transient, as values decreased rapidly in the first 10 minutes, and as a group declined more gradually to the 90-minute time point, after which FF stabilized (Figure 4 above). These findings were maintained even when removing those who did not complete the full duration of cooling from the analysis (Appendix Section 7.3.4). As aforementioned, two independent studies have presented individualized time course plots of BAT FF changes during cold activationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-2","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"^56,74","plainTextFormattedCitation":"56,74","previouslyFormattedCitation":"^56,74"},"properties":{"noteIndex":0},"schema":""}56,74. Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 used a water-perfused vest to deliver a 12°C exposure for 90 minutes in a cohort of 10 normal weight individuals (5 males and 5 females) under the age of 30. The individual time course plots of changes in FF within iBAT, a region not associated with active BAT in adults, present with noticeable intersubject variability that makes generalization difficult. Nonetheless, there was an apparent decrease in FF, which was more pronounced in some individuals, over the course of the 90-minute cold exposure. Most of these changes appeared to occur within the first hour, after which FF values stabilized (see Appendix Section 7.1, subjects S01, S03, S04, S09 for examples). McCallister et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁴","plainTextFormattedCitation":"74","previouslyFormattedCitation":"⁷⁴"},"properties":{"noteIndex":0},"schema":""}74 included a similar population in their study design – however SCV BAT FF was measured over the course of a 150-minute cold exposure delivered via water-perfused pads. Individual time course plots of FF (Appendix Section 7.1) are also difficult to interpret as cold exposure duration and scanning intervals varied across participants. Of those presented, 2 participants experienced a gradual decline in FF throughout (subjects A and E), 2 exhibited an initial decline followed by a recovery towards baseline (subjects B and F), and two underwent no apparent cold-induced changes (subjects C and G)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁴","plainTextFormattedCitation":"74","previouslyFormattedCitation":"⁷⁴"},"properties":{"noteIndex":0},"schema":""}74. In the present study, a measurable decline in the SCV BAT FF during the early phases of cooling was visually apparent for all subjects (see Appendix Section 7.3.1 for individual time course plots). However, these attempts at identifying a time course of change in BAT FF during cooling are particularly heterogeneous with respect to segmentation of the BAT ROI (i.e. interscapular versus SCV region, FF thresholds, and presence/absence of a secondary threshold such as T2* or FDG uptake; see Section 1.5.1.1 above), and therefore such comparisons should be interpreted with caution. A meaningful reduction in FF was detected as soon as 10 minutes following the onset of cold exposure (mean difference = -1.6%; p=0.005), and various independent research groups using multiple modalities of detection have also observed a rapid BAT-specific response to a sympathetic stimulus. In humans, Haq et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42 observed a maximal increase in SCV skin temperature, as measured using infrared thermography (IRT), after only 10 minutes of a 12°C cold exposure in a cohort of young adult males. Garretson et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.molmet.2016.06.013","ISSN":"2212-8778","author":[{"dropping-particle":"","family":"Garretson","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szymanski","given":"Laura A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"Gary J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Metabolism","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"626-634","publisher":"Elsevier GmbH","title":"Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁴","plainTextFormattedCitation":"94","previouslyFormattedCitation":"⁹⁴"},"properties":{"noteIndex":0},"schema":""}94 also reported a significant temperature change in the skin overlying the iBAT of Siberian hamsters within 5 minutes of CL-316,243 injection. Regardless of the chosen method of stimulation, this finding has been consistent among other studies which measured BAT-specific temperature changesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2012.04.056","ISBN":"1097-6833 (Electronic)\\n0022-3476 (Linking)","ISSN":"00223476","PMID":"22677567","abstract":"Objective: To establish the feasibility of infrared thermal imaging as a reproducible, noninvasive method for assessing changes in skin temperature within the supraclavicular region in vivo. Study design: Thermal imaging was used to assess the effect of a standard cool challenge (by placement of the participant's feet or hand in water at 20°C) on the temperature of the supraclavicular region in healthy volunteer participants of normal body mass index in 3 age groups, 3-8, 13-18, and 35-58 years of age. Results: We demonstrated a highly localized increase in temperature within the supraclavicular region together with a significant age-related decline under both baseline and stimulated conditions. Conclusion: Thermogenesis within the supraclavicular region can be readily quantified by thermal imaging. This noninvasive imaging technique now has the potential to be used to assess brown adipose tissue function alone, or in combination with other techniques, in order to determine the roles of thermogenesis in energy balance and, therefore, obesity prevention. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Symonds","given":"Michael E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henderson","given":"Katrina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elvidge","given":"Lindsay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bosman","given":"Conrad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharkey","given":"Don","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Alan C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Budge","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"892-898","publisher":"Mosby, Inc.","title":"Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children","type":"article-journal","volume":"161"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jpeds.2013.10.005","ISSN":"00223476","abstract":"Objective To determine whether body mass index (BMI) percentile and ethnicity influence skin temperature overlying brown adipose tissue (BAT) depots in the supraclavicular region in healthy children. Study design Infrared thermography measured supraclavicular region temperature (TSCR) at baseline and after exposure to a mild cool stimulus (single hand immersion in water at 20.1 C) for 5 minutes in children aged 6-11 years (n = 55). The studies were undertaken in a normal school environment. Results BMI percentile and ethnicity were significant predictors of baseline TSCR, with an inverse relationship between BMI percentile persisting after adjustment for ethnicity. Twenty-four children demonstrated a significant rise in T SCR after exposure to the cool stimulus. BMI percentile was a significant predictor of TSCR response, although there was no effect of ethnicity on TSCR change after exposure to the cool stimulus. Conclusion We have demonstrated a negative relationship between BMI percentile and both baseline TSCR, colocating with the primary region of BAT, and the change in TSCR in response to the cool stimulus. Future studies aimed at determining the primary factors regulating BAT function in healthy children should be targeted at the goal of maintaining a healthy BMI trajectory during childhood.","author":[{"dropping-particle":"","family":"Robinson","given":"Lindsay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ojha","given":"Shalini","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Symonds","given":"Michael E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Budge","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2014"]]},"page":"318-322.e1","publisher":"Elsevier Ltd","title":"Body mass index as a determinant of brown adipose tissue function in healthy children","type":"article-journal","volume":"164"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1007/s12576-016-0472-1","ISBN":"1880-6546, 1880-6562","ISSN":"18806546","PMID":"27443171","abstract":"The ability to alter the amount and activity of brown adipose tissue (BAT) in human adults is a potential strategy to manage obesity and related metabolic disorders associated with food, drug, and environmental stimuli with BAT activating/recruiting capacity. Infrared thermography (IRT) provides a non-invasive and inexpensive alternative to the current methods (e.g. (18)F-FDG PET) used to assess BAT. We have quantified BAT activation in the cervical-supraclavicular (C-SCV) region using IRT video imaging and a novel image computational algorithm by studying C-SCV heat production in healthy young men after cold stimulation and the ingestion of capsinoids in a prospective double-blind placebo-controlled randomized trial. Subjects were divided into low-BAT and high-BAT groups based on changes in IR emissions in the C-SCV region induced by cold. The high-BAT group showed significant increases in energy expenditure, fat oxidation, and heat output in the C-SCV region post-capsinoid ingestion compared to post-placebo ingestion, but the low-BAT group did not. Based on these results, we conclude that IRT is a promising tool for quantifying BAT activity.","author":[{"dropping-particle":"","family":"Ang","given":"Qi Yan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goh","given":"Hui Jen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Yanpeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Yiqun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chan","given":"Siew Pang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swain","given":"Judith L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henry","given":"Christiani Jeyakumar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leow","given":"Melvin Khee Shing","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Physiological Sciences","id":"ITEM-3","issued":{"date-parts":[["2016"]]},"page":"1-12","publisher":"Springer Japan","title":"A new method of infrared thermography for quantification of brown adipose tissue activation in healthy adults (TACTICAL): a randomized trial","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^95–97","plainTextFormattedCitation":"95–97","previouslyFormattedCitation":"^95–97"},"properties":{"noteIndex":0},"schema":""}95–97. At the molecular level, Motillo and colleagesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1074/jbc.M112.374041","ISBN":"4431987398","author":[{"dropping-particle":"","family":"Mottillo","given":"Emilio P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bloch","given":"Ainsley E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leff","given":"Todd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neurosciences","given":"Behavioral","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Biological Chemistry","id":"ITEM-1","issue":"30","issued":{"date-parts":[["2012"]]},"page":"25038-25048","title":"Lipolytic Products Activate Peroxisome Proliferator-activated Receptor ( PPAR ) aplha and delta in Brown Adipocytes to Match Fatty Acid Oxidation with Supply","type":"article-journal","volume":"287"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁸","plainTextFormattedCitation":"98","previouslyFormattedCitation":"⁹⁸"},"properties":{"noteIndex":0},"schema":""}98 used animal models and in vivo experiments to observe the appearance of ligands for PPAR-gamma (i.e. prefacing intracellular lipolysis and eventual UCP1 action) at BAT lipid droplet surfaces within minutes of stimulation. Therefore, the connection between substrate mobilization and oxidation appears almost instantaneously. 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Therefore, results of previous investigations in both humans and animals are complementary to the present study in that BAT measurements consistently show an immediate, yet temporary response to a stimulus. Thus, a shorter duration of cold exposure may be considered in future studies using MRI to detect BAT activity, as this could increase the feasibility of gathering larger and younger sample populations.Since FF is dictated by the relative amounts of fat and water within a tissue, an increase in the latter following BAT stimulation could contribute to the present findings. The unique morphology of BAT includes a dense system of vasculature to both deliver substrate and dissipate heat upon activationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. Therefore an increase in tissue perfusion (i.e. increase in water content) and concomitant decrease in intracellular fat content are likely to be both implicated in the observed decrease SCV BAT FF. Panagia et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3557","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"27226402","abstract":"Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the beta3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 +/- 1 mm3 versus 65 +/- 3 mm3 ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Panagia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Y I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"H H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ernande","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sosnovik","given":"D E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR Biomed","id":"ITEM-1","issue":"October 2015","issued":{"date-parts":[["2016"]]},"page":"978-984","title":"Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁶","plainTextFormattedCitation":"106","previouslyFormattedCitation":"¹⁰⁶"},"properties":{"noteIndex":0},"schema":""}106 used blood-oxygen-level dependent (BOLD) imaging (based on changes in T2* signaling, which is a tissue-specific MRI property that is sensitive to the relative amounts of deoxyHb and oxyHb in a tissue where an increase in the former, such as during BAT activation, decreases T2* valuesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.22162.","ISBN":"8585348585","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"DL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"KS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goran","given":"MI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy","given":"TR","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2010"]]},"page":"1195-1202","title":"Identification of Brown Adipose Tissue in Mice with Fat-Water IDEAL-MRI","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵³","plainTextFormattedCitation":"53","previouslyFormattedCitation":"⁵³"},"properties":{"noteIndex":0},"schema":""}53) to measure the response in the iBAT of mice subjected to a beta-adrenergic agonist. Briefly, there was an immediate but transient spike in BOLD signal, suggesting that the initial BAT response to stimulation might be dominated by increased blood flow rather than lipid consumptionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3557","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"27226402","abstract":"Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the beta3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 +/- 1 mm3 versus 65 +/- 3 mm3 ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Panagia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Y I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"H H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ernande","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sosnovik","given":"D E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR Biomed","id":"ITEM-1","issue":"October 2015","issued":{"date-parts":[["2016"]]},"page":"978-984","title":"Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁶","plainTextFormattedCitation":"106","previouslyFormattedCitation":"¹⁰⁶"},"properties":{"noteIndex":0},"schema":""}106. This finding was repeated by Reeder et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2018.02.002","ISSN":"19327420","PMID":"29514074","abstract":"Metabolism is a fundamental process of life. However, non-invasive measurement of local tissue metabolism is limited today by a deficiency in adequate tools for in vivo observations. We designed a multi-modular platform that explored the relation between local tissue oxygen consumption, determined by label-free optoacoustic measurements of hemoglobin, and concurrent indirect calorimetry obtained during metabolic activation of brown adipose tissue (BAT). By studying mice and humans, we show how video-rate handheld multi-spectral optoacoustic tomography (MSOT) in the 700–970 nm spectral range enables non-invasive imaging of BAT activation, consistent with positron emission tomography findings. Moreover, we observe BAT composition differences between healthy and diabetic tissues. The study consolidates hemoglobin as a principal label-free biomarker for longitudinal non-invasive imaging of BAT morphology and bioenergetics in situ. We also resolve water and fat components in volunteers, and contrast MSOT readouts with magnetic resonance imaging data. Reber et al. employed label-free multi-spectral optoacoustic tomography to non-invasively image BAT and WAT in mice and humans and resolve BAT activation based on hemoglobin gradients. The 700–970 nm spectral range further enabled identification of BAT composition using lipid and water signatures.","author":[{"dropping-particle":"","family":"Reber","given":"Josefine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Willersh?user","given":"Monja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karlas","given":"Angelos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paul-Yuan","given":"Korbinian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diot","given":"Gael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franz","given":"Daniela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fromme","given":"Tobias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Ovsepian","given":"Saak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bézière","given":"Nicolas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dubikovskaya","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karampinos","given":"Dimitrios C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holzapfel","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hauner","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klingenspor","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ntziachristos","given":"Vasilis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"689-701","title":"Non-invasive Measurement of Brown Fat Metabolism Based on Optoacoustic Imaging of Hemoglobin Gradients","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁷","plainTextFormattedCitation":"107","previouslyFormattedCitation":"¹⁰⁷"},"properties":{"noteIndex":0},"schema":""}107 and Van Rooijen et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁷","plainTextFormattedCitation":"67","previouslyFormattedCitation":"⁶⁷"},"properties":{"noteIndex":0},"schema":""}67, who both noted a brief spike in oxyHb levels within the SCV BAT of a small cohort of human subjects during acute bouts of cold exposure, which furthers the previous analysis by showing the speed at which oxygen is consumed by BAT. Individual variation in cardiac output and heart rate could also implicate the supposed acute increase in blood flow to BAT – however, this relationship is currently unclearADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.echo.2015.06.014","ISBN":"1097-6795 (Electronic)\\r0894-7317 (Linking)","ISSN":"10976795","PMID":"26255029","abstract":"Background Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT). The investigators recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). Here, they report the application of this method in healthy humans. Methods Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (??) of microbubble replenishment curves. All underwent 18F-FDG PET/CT after cold exposure. Results An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by 18F-FDG PET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median A?? = 3.3 AU/s [interquartile range, 0.5-5.7 AU/s] vs 1.25 AU/s [interquartile range, 0.5-2.6 AU/s]; P =.02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by 18F-FDG PET/CT (median maximal standardized uptake value, 2.25 [interquartile range, 1.53-4.57] vs 0.51 [interquartile range, 0.47-0.73]; P =.02). Conclusions The present study demonstrates the feasibility of using CEUS as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies.","author":[{"dropping-particle":"","family":"Flynn","given":"Aidan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Qian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Panagia","given":"Marcello","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdelbaky","given":"Amr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Macnabb","given":"Megan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samir","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weyman","given":"Arthur E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tawakol","given":"Ahmed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"Marielle","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Echocardiography","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1247-1254","publisher":"Elsevier Inc","title":"Contrast-Enhanced Ultrasound: A Novel Noninvasive, Nonionizing Method for the Detection of Brown Adipose Tissue in Humans","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁸","plainTextFormattedCitation":"108","previouslyFormattedCitation":"¹⁰⁸"},"properties":{"noteIndex":0},"schema":""}108. Therefore, these findings in combination with the time course of change in SCV BAT T2* (Figure 15 in Appendix Section 7.3.3) deduced by the present study suggests that FF could be influenced by water more so than fat during the initial phases of cold exposure, but likely not after prolonged stimulation.Rate of change in SCV BAT FF during coolingThe rate of change in SCV BAT FF during the time course transitioned from a net negative slope (i.e. decrease in FF) to stabilization around the x-axis (i.e. no change in FF) at around 90 minutes from the onset of cold exposure. This finding is in line with the above in that changes in BAT were transient, and therefore no further discussion is warranted. To the best of my knowledge, Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 was the only time course study in humans that reported the rate of cold-induced change in BAT FF. In particular, Figure 5 from this publication presented slopes (FF%/hour) for five males under the age of 30 that were included in their analysis. Among these individuals, FF decreased by ~0.8 to ~6%/hour, which is within the range of values for this analysis (Table 6 below):Table SEQ Table \* ARABIC 6 - Rate of change in FF from 0-60 minutes of cold exposure (%/hour)SUBJECT123456789101112SLOPE-3.7-4.2-1.9-8.1-0.9-5.0-1.2-8.3-6.1-1.6-6.0-4.6Notable differences between the methodologies of Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 and the present study, namely the BAT depot of interest (i.e. interscapular versus SCV) and cold exposure protocol (i.e. water-perfused vest at 12°C and whole-body water-perfused suit at 18°C), should be considered when interpreting the above notion. Altogether, the rate of change in a BAT-specific measurement during acute activation is absent within the literature and should therefore be highlighted by future studies.Mathematically describing the change in FF over timeA preliminary model describing the change in SCV BAT FF over time was deduced from this small dataset of male subjects under the age of 30, which enhances the generalizability of the present findings. In particular, one can use this equation to predict the measured FF value at any given time point – however it is important to remain cautious of the study population of concern, the BAT depot of interest, and the cooling protocol used when interpreting the results. Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 proposed a mean FF reduction of 2.9% after one hour of cold exposure, which is comparable to the 2.6% that was mathematically derived from our quadratic formula. This similarity exists despite large variations in cooling protocols and BAT ROI selections. Furthermore, Gifford et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶³","plainTextFormattedCitation":"63","previouslyFormattedCitation":"⁶³"},"properties":{"noteIndex":0},"schema":""}63 and Holstila et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.metabol.2017.02.001","ISSN":"00260495","PMID":"28403942","author":[{"dropping-particle":"","family":"Holstila","given":"Milja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pesola","given":"Marko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Borra","given":"Ronald J.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"23-30","publisher":"Elsevier Inc.","title":"MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure","type":"article-journal","volume":"70"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁰","plainTextFormattedCitation":"70","previouslyFormattedCitation":"⁷⁰"},"properties":{"noteIndex":0},"schema":""}70 measured a mean SCV BAT FF decrease of 2.2% and 0.4%, respectively, after two hours of cooling. Both are considerably less than what would be predicated using our model (i.e. 3.74%), which might again be attributed to the inherent differences between methodologies (i.e. older versus younger populations, lean versus obese populations, whole-body versus targeted cold exposure, etc.)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"103-113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁹","plainTextFormattedCitation":"49","previouslyFormattedCitation":"⁴⁹"},"properties":{"noteIndex":0},"schema":""}49.Further, a relationship that is quadratic in nature assumes that at some point, values begin to trend in the opposite direction (i.e. there is a point of inflection). One can observe that in the time course of SCV BAT FF (Figure 4), measurements appeared to inflect towards baseline within the last hour of cold exposure, which the quadratic formula identified as 150 minutes. In addition to the physiological implications of substrate availability and use (discussed below) , this pattern might be related to a homeostatic mechanism in which thermal receptors become desensitized to a constant stimulusADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Hall","given":"J.E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"edition":"13","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"publisher":"Saunders","publisher-place":"St. Louis","title":"Guyton and Hall Textbook of Medical Physiology","type":"book"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁹","plainTextFormattedCitation":"109","previouslyFormattedCitation":"¹⁰⁹"},"properties":{"noteIndex":0},"schema":""}109. Following an initial, strong, discharge at the beginning of a stimulus, the response progressively weakens and eventually ceases altogetherADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Hall","given":"J.E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"edition":"13","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"publisher":"Saunders","publisher-place":"St. Louis","title":"Guyton and Hall Textbook of Medical Physiology","type":"book"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁹","plainTextFormattedCitation":"109","previouslyFormattedCitation":"¹⁰⁹"},"properties":{"noteIndex":0},"schema":""}109.Lastly, obtaining a rho value (i.e. ICC) of 0.96 when considering each individual as a unique cluster suggests that the overall variability in FF over time depends largely on between-subject differences. These differences may pertain to one’s relative dependency on shivering and non-shivering thermogenesis for whole-body heat productionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"00219738 15588238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical investigation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"545","title":"Brown adipose tissue oxidative metabolism contributles to energy expenditure during cold exposure in humans","type":"article-journal","volume":"122"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-2","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.cmet.2016.12.005","ISSN":"19327420","PMID":"28089568","abstract":"Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11C-acetate and 18F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C. Andre C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C. Andre C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-3","issue":"2","issued":{"date-parts":[["2017"]]},"page":"438-447","title":"Inhibition of Intracellular Triglyceride Lipolysis Suppresses Cold-Induced Brown Adipose Tissue Metabolism and Increases Shivering in Humans","type":"article-journal","volume":"25"},"uris":[""]}],"mendeley":{"formattedCitation":"^11,50,78","plainTextFormattedCitation":"11,50,78","previouslyFormattedCitation":"^11,50,78"},"properties":{"noteIndex":0},"schema":""}11,50,78, which will be addressed in Section 5.2 below. A hypothesized physiological explanation for the time course of fuel utilization during BAT NSTThough the pattern of change in FF may in part be attributed to the small sample size and random noise that is inherent in MRI signals, it might provide insight into the interplay between fuel sources during BAT NST. In brief, a seminal review by Cannon and Nedergaard suggested that bouts of BAT activity, as measured by continuous NE turnover, may be much shorter than several hours, and that the degree of recruitment is limited by the amount of BAT tissue one has at baselineADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. Given that Motillo et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1074/jbc.M112.374041","ISBN":"4431987398","author":[{"dropping-particle":"","family":"Mottillo","given":"Emilio P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bloch","given":"Ainsley E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leff","given":"Todd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neurosciences","given":"Behavioral","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Biological Chemistry","id":"ITEM-1","issue":"30","issued":{"date-parts":[["2012"]]},"page":"25038-25048","title":"Lipolytic Products Activate Peroxisome Proliferator-activated Receptor ( PPAR ) aplha and delta in Brown Adipocytes to Match Fatty Acid Oxidation with Supply","type":"article-journal","volume":"287"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁸","plainTextFormattedCitation":"98","previouslyFormattedCitation":"⁹⁸"},"properties":{"noteIndex":0},"schema":""}98 suggested a time lag of mere minutes between the formation of lipolysis products and induction of oxidative genes in BAT, and that in vitro experiments identified lipogenesis from exogenous FFAsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor 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{"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"15-30","title":"Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"Gliemann","given":"Jorgen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gammeltoft","given":"Steen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vinten","given":"Jorgen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Biological Chemistry","id":"ITEM-2","issue":"9","issued":{"date-parts":[["1976"]]},"page":"3368-3374","title":"Time Course of Insulin-Receptor Binding and Insulin-induced Lipogenesis in Isolated Rat Fat Cells","type":"article-journal","volume":"250"},"uris":[""]},{"id":"ITEM-3","itemData":{"author":[{"dropping-particle":"","family":"Weiss","given":"Samuel B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kennedy","given":"Eugene 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It remains uncertain whether BAT (18)F-FDG uptake reliably tracks UCP1-mediated heat production. METHODS UCP1 knockout (UCP1 KO) and wild-type mice received the selective β3 adrenergic receptor agonist CL 316, 243 (1mg/kg) and underwent metabolic cage, infrared thermal imaging and (18)F-FDG PET/magnetic resonance imaging (MRI) experiments. Primary brown adipocytes were additionally examined for their bioenergetics as well as their uptake of 2-deoxy-3H-glucose. RESULTS In response to CL 316, 243 treatments, oxygen consumption and BAT thermogenesis were diminished in UCP1 KO mice but BAT (18)F-FDG uptake was fully retained. UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-3H-glucose uptake rates were largely unaffected. CONCLUSION Increased BAT (18)F-FDG uptake can occur independently of UCP1 function.","author":[{"dropping-particle":"","family":"Hankir","given":"Mohammed K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kranz","given":"Mathias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keipert","given":"Susanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"Juliane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreasen","given":"Sille G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kern","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patt","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kl?ting","given":"Nora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heiker","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hesse","given":"Swen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brust","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jastroch","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fenske","given":"Wiebke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-4","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"jnumed.116.186460","title":"Dissociation between brown adipose tissue 18 F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice","type":"article-journal"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.cmet.2017.10.008","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Sanchez-Gurmaches","given":"Joan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Yuefeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jespersen","given":"Naja Zenius","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallace","given":"Martina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calejman","given":"Camila Martinez","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gujja","given":"Sharvari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Huawei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Edwards","given":"Yvonne J.K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfrum","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Metallo","given":"Christian M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"S?ren","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scheele","given":"Camilla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guertin","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-5","issue":"1","issued":{"date-parts":[["2018"]]},"page":"1-15","publisher":"Elsevier Inc.","title":"Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"^{25,28,110–112}","plainTextFormattedCitation":"25,28,110–112","previouslyFormattedCitation":"^{25,28,110–112}"},"properties":{"noteIndex":0},"schema":""}25,28,110–112 as a rapid and frequent process (i.e. minutes), it is reasonable to postulate that a three hour cold exposure would present multiple transitions between intracellular TAG depletion and resurgence. A well-supported notion is that BAT NST is fueled preferentially by FFAs liberated from intracellular TAG poolsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60941","ISBN":"1558-8238 (Electronic)\\n0021-9738 (Linking)","ISSN":"00219738","PMID":"22269320","abstract":"That adult humans possess brown fat is now accepted - but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity - provided that brown fat becomes activated not only by cold but also through food-related stimuli.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"486-489","title":"Yes, even human brown fat is on fire!","type":"article-journal","volume":"122"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1172/JCI60433DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"00219738 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Given that in the present study there was an initial decrease in FF over the 90 minutes of cold exposure, this might suggest that stored TAGs were used during this time period. Since FF appeared to be maintained beyond this point, BAT might indeed be drawing on exogenous substrates to fuel thermogenesis during prolonged activation. Glucose is one such substrate that can directly (i.e. oxidation during uncoupled respirationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-018-27875-3","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Held","given":"Ntsiki M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuipers","given":"Eline N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Weeghel","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Klinken","given":"Jan Bert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simone","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lombès","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wanders","given":"Ronald J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaz","given":"Frédéric M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verhoeven","given":"Arthur J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boon","given":"Mari?tte R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Houtkooper","given":"Riekelt H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"9562","issued":{"date-parts":[["2018"]]},"page":"1-12","title":"Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁷","plainTextFormattedCitation":"27","previouslyFormattedCitation":"²⁷"},"properties":{"noteIndex":0},"schema":""}27) or indirectly (i.e. conversion to G3P to replenish the TAG reserves in BAT) contribute to BAT NST. With regards to the latter idea, animal studies suggest that glucose-derived de novo FA are compartmentalized rapidly into a distinct pool of TAG that are almost instantaneously oxidizedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.116.186460","ISBN":"4934197133","ISSN":"0161-5505","PMID":"28082439","abstract":"(18)F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain whether BAT (18)F-FDG uptake reliably tracks UCP1-mediated heat production. METHODS UCP1 knockout (UCP1 KO) and wild-type mice received the selective β3 adrenergic receptor agonist CL 316, 243 (1mg/kg) and underwent metabolic cage, infrared thermal imaging and (18)F-FDG PET/magnetic resonance imaging (MRI) experiments. Primary brown adipocytes were additionally examined for their bioenergetics as well as their uptake of 2-deoxy-3H-glucose. RESULTS In response to CL 316, 243 treatments, oxygen consumption and BAT thermogenesis were diminished in UCP1 KO mice but BAT (18)F-FDG uptake was fully retained. UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-3H-glucose uptake rates were largely unaffected. CONCLUSION Increased BAT (18)F-FDG uptake can occur independently of UCP1 function.","author":[{"dropping-particle":"","family":"Hankir","given":"Mohammed K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kranz","given":"Mathias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Keipert","given":"Susanne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"Juliane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Andreasen","given":"Sille G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kern","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patt","given":"Marianne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kl?ting","given":"Nora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heiker","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hesse","given":"Swen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brust","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jastroch","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fenske","given":"Wiebke","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"jnumed.116.186460","title":"Dissociation between brown adipose tissue 18 F-FDG uptake and thermogenesis in uncoupling protein 1 deficient mice","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"15-30","title":"Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1038/s41598-018-27875-3","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Held","given":"Ntsiki M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuipers","given":"Eline N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Weeghel","given":"Michel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van","family":"Klinken","given":"Jan Bert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simone","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lombès","given":"Marc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wanders","given":"Ronald J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaz","given":"Frédéric M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verhoeven","given":"Arthur J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boon","given":"Mari?tte R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Houtkooper","given":"Riekelt H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-3","issue":"9562","issued":{"date-parts":[["2018"]]},"page":"1-12","title":"Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"^25,27,28","plainTextFormattedCitation":"25,27,28","previouslyFormattedCitation":"^25,27,28"},"properties":{"noteIndex":0},"schema":""}25,27,28. The high turnover of this distinct pool of TAGs might explain the lack of observed change in FF during the latter phases of cold exposure. Furthermore, glucose uptake into BAT is controlled via negative wherein an increase in lipolysis and a decrease in intraceullar TAG content promotes exogenous substrate utilizationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"15-30","title":"Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes","type":"article-journal","volume":"58"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"^20,28","plainTextFormattedCitation":"20,28","previouslyFormattedCitation":"^20,28"},"properties":{"noteIndex":0},"schema":""}20,28. In addition to glucose, there is evidence suggesting that activated BAT draws directly on exogenous FFAs to sustain thermogenesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6. Though dietary FFAs are one source of such fuelADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ncomms14146","ISSN":"2041-1723","PMID":"28134339","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"14146","title":"Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men","type":"article-journal","volume":"8"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2017.09.002","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Shin","given":"Hyunsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Yinyan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chanturiya","given":"Tatyana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Qiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Youlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kadegowda","given":"Anil K G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jackson","given":"Rachel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rumore","given":"Dominic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gavrilova","given":"Oksana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Liqing","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1-14","publisher":"Elsevier Inc.","title":"Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"^114,115","plainTextFormattedCitation":"114,115","previouslyFormattedCitation":"^114,115"},"properties":{"noteIndex":0},"schema":""}114,115 and therefore could be implicated in the pattern of change in FF, the participants in the present study were exposed to cold in a fasted state. As such, the subjects might have relied more on FFA liberated from circulating triglyceride rich proteins (TRLs)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2011.00084","ISBN":"1664-2392 (Electronic)\\r1664-2392 (Linking)","ISSN":"1664-2392","PMID":"22654830","abstract":"Brown adipose tissue (BAT) non-shivering thermogenesis impacts energy homeostasis in rodents and humans. Mitochondrial uncoupling protein 1 in brown fat cells produces heat by dissipating the energy generated by fatty acid and glucose oxidation. In addition to thermogenesis and despite its small relative size, sympathetically activated BAT constitutes an important glucose, fatty acid, and triacylglycerol-clearing organ, and such function could potentially be used to alleviate dyslipidemias, hyperglycemia, and insulin resistance. To date, chronic sympathetic innervation and peroxisome proliferator-activated receptor (PPAR) γ activation are the only recognized inducers of BAT recruitment. Here, we review the major differences between these two BAT inducers in the regulation of lipolysis, fatty acid oxidation, lipid uptake and triacylglycerol synthesis, glucose uptake, and de novo lipogenesis. Whereas BAT recruitment through sympathetic drive translates into functional thermogenic activity, PPARγ-mediated recruitment is associated with a reduction in sympathetic activity leading to increased lipid storage in brown adipocytes. The promising therapeutic role of BAT in the treatment of hypertriglyceridemic and hyperglycemic conditions is also discussed.","author":[{"dropping-particle":"","family":"Festuccia","given":"William T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blanchard","given":"Pierre-Gilles","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deshaies","given":"Yves","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"December","issued":{"date-parts":[["2011"]]},"page":"1-6","title":"Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ.","type":"article-journal","volume":"2"},"uris":[""]}],"mendeley":{"formattedCitation":"¹","plainTextFormattedCitation":"1","previouslyFormattedCitation":"¹"},"properties":{"noteIndex":0},"schema":""}1 and/or sympathetically activated WAT depotsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.molmet.2016.06.013","ISSN":"2212-8778","author":[{"dropping-particle":"","family":"Garretson","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szymanski","given":"Laura A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"Gary J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Metabolism","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"626-634","publisher":"Elsevier GmbH","title":"Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis","type":"article-journal","volume":"5"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2017.09.002","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Shin","given":"Hyunsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Yinyan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chanturiya","given":"Tatyana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Qiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Youlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kadegowda","given":"Anil K G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jackson","given":"Rachel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rumore","given":"Dominic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gavrilova","given":"Oksana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Liqing","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1-14","publisher":"Elsevier Inc.","title":"Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"^94,115","plainTextFormattedCitation":"94,115","previouslyFormattedCitation":"^94,115"},"properties":{"noteIndex":0},"schema":""}94,115. Specifically, Bartelt et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nm.2297","ISBN":"1546-170X (Electronic)\\r1078-8956 (Linking)","ISSN":"1546-170X","PMID":"21258337","abstract":"Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.","author":[{"dropping-particle":"","family":"Bartelt","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruns","given":"O T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reimer","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohenberg","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ittrich","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Peldschus","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaul","given":"M G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tromsdorf","given":"U I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weller","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Waurisch","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eychmuller","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordts","given":"P L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rinninger","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bruegelmann","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freund","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Merkel","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heeren","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nat Med","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2011"]]},"page":"200-205","publisher":"Nature Publishing Group","title":"Brown adipose tissue activity controls triglyceride clearance","type":"article-journal","volume":"17"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³","plainTextFormattedCitation":"13","previouslyFormattedCitation":"¹³"},"properties":{"noteIndex":0},"schema":""}13 found increased LPL in the iBAT vasculature of cold-exposed mice, which translates to two important outcomes: 1) local LPL activity in BAT is required for exogenous FFA uptake, and 2) LPL activity increases vascular permeability and permits the internalization of TRLsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ijo.2010.182.Sympathetic","author":[{"dropping-particle":"","family":"Bartness","given":"TJ","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vaughan","given":"CH","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Song","given":"CK","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issue":"Suppl","issued":{"date-parts":[["2010"]]},"note":"NULL","page":"S36-42","title":"Sympathetic and sensory innervation of brown adipose tissue","type":"article-journal","volume":"34"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁶","plainTextFormattedCitation":"116","previouslyFormattedCitation":"¹¹⁶"},"properties":{"noteIndex":0},"schema":""}116. There is also an abundance of evidence suggesting that whole-body WAT lipolysis is essential for sustained BAT activityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fendo.2015.00156","ISBN":"1664-2392","ISSN":"16642392","PMID":"26528238","abstract":"Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized.","author":[{"dropping-particle":"","family":"Porter","given":"Craig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chondronikola","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sidossis","given":"Labros S.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Endocrinology","id":"ITEM-1","issue":"OCT","issued":{"date-parts":[["2015"]]},"page":"1-8","title":"The therapeutic potential of brown adipocytes in humans","type":"article-journal","volume":"6"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2014.12.009.Activation","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"Lauren S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts-toler","given":"Carla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elía","given":"Elisa Franquet","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kessler","given":"H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"Peter A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"English","given":"Jeffrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chatman","given":"Kelly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Trauger","given":"Sunia A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doria","given":"Alessandro","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2015"]]},"note":"From Duplicate 2 (Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist - Cypess, Aaron M; Weiner, Lauren S; Roberts-toler, Carla; Elía, Elisa Franquet; Kessler, H; Kahn, Peter A; English, Jeffrey; Chatman, Kelly; Trauger, Sunia A; Doria, Alessandro; Kolodny, Gerald M)\n\nNULL","page":"33-38","title":"Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist","type":"article-journal","volume":"21"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André 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Among these studies, Shin et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.002","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Shin","given":"Hyunsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Yinyan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chanturiya","given":"Tatyana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Qiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Youlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kadegowda","given":"Anil K G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jackson","given":"Rachel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rumore","given":"Dominic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gavrilova","given":"Oksana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Liqing","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1-14","publisher":"Elsevier Inc.","title":"Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁵","plainTextFormattedCitation":"115","previouslyFormattedCitation":"¹¹⁵"},"properties":{"noteIndex":0},"schema":""}115 and Schreiber et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sedej","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-763.e7","publisher":"Elsevier Inc.","title":"Cold-Induced Thermogenesis Depends on ATGL- Mediated Lipolysis in Cardiac Muscle, but Not Brown","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁸","plainTextFormattedCitation":"118","previouslyFormattedCitation":"¹¹⁸"},"properties":{"noteIndex":0},"schema":""}118 were the most convincing as they independently showed reduced cold tolerance in mice with global deactivation of lipolysis compared to animals with defective lipolysis only in BAT. Furthermore, Lynes et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nm.4297","ISSN":"1078-8956","PMID":"28346411","author":[{"dropping-particle":"","family":"Lynes","given":"Matthew D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiria","given":"Luiz O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lundh","given":"Morten","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartelt","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shamsi","given":"Farnaz","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"Tian Lian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Takahashi","given":"Hirokazu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirshman","given":"Michael F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schlein","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Alexandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baer","given":"Lisa A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"May","given":"Francis J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gao","given":"Fei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Narain","given":"Niven R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Emily Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kiebish","given":"Michael A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blüher","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goodyear","given":"Laurie J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hotamisligil","given":"G?khan S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stanford","given":"Kristin I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tseng","given":"Yu-Hua","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁹","plainTextFormattedCitation":"119","previouslyFormattedCitation":"¹¹⁹"},"properties":{"noteIndex":0},"schema":""}119 introduced 12,13-diHOME as a “batokine” that acts in an autocrine-paracrine manner to further augment FA uptake into BAT during cold activation. These exogenous FA, unlike glucose-derived TAGs, are distinctly stored in a larger and less transient pool of TAGs,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1194/jlr.M068197","author":[{"dropping-particle":"","family":"Irshad","given":"Zehra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitri","given":"Federica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Christian","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zammit","given":"Victor A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"15-30","title":"Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes","type":"article-journal","volume":"58"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁸","plainTextFormattedCitation":"28","previouslyFormattedCitation":"²⁸"},"properties":{"noteIndex":0},"schema":""}28 potentially contributing to the slight recovery of FF towards the end of cold exposure that was observed in the present study (see Figure 22 in Appendix Section 7.4 for a proposed model summarizing the time course of fuel use during BAT activation). Nonetheless, whether or not the observed signal fluctuations are due to the inherent limitations in MRI or the dynamic nature of BAT fuel use is certainly up for debate.Time Course of Change in Posterior Neck SAT FF Over CoolingThe posterior neck SAT, a region not generally referred to as a source of significant NST in adult humansADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00259-016-3364-y","ISSN":"1619-7070","author":[{"dropping-particle":"","family":"Din","given":"Mueez","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kudomi","given":"Nobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tolvanen","given":"Tuula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oikonen","given":"Vesa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teuho","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sipila","given":"HT","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Savisto","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2016"]]},"page":"1878-1886","publisher":"European Journal of Nuclear Medicine and Molecular Imaging","title":"Human brown adipose tissue [15O]O2 PET imaging in the presence and absence of cold stimulus","type":"article-journal","volume":"43"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"^67,120","plainTextFormattedCitation":"67,120","previouslyFormattedCitation":"¹²⁰"},"properties":{"noteIndex":0},"schema":""}67,120, was measured alongside SCV BAT FF during cooling. As seen in Figure 6A-C above, cold did not induce considerable changes in FF throughout the time course in this adipose depot. However, there was a measurable, albeit non-significant, decrease from baseline as time proceeded (mean±SD of maximal FF reduction = 1.1±2.0%). This was particularly observable in some participants (namely 071, 072, and 074, Appendix Section 7.3.1), as the pattern of change in posterior neck SAT FF mirrored SCV BAT FF. Coincidentally, these participants had a lean BMI and low % body fat (range: 19.8-22.4 kg/m2 and 15.6-21.2%, respectively), a phenotype which is known to be associated with an augmented whole-body lipolytic response as a result of a sympathetic stimulus, such as coldADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.immuni.2010.12.017.Two-stage","ISBN":"6176321972","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shrestha","given":"Yogendra B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Neuroendocrinology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"note":"NULL","page":"473-493","title":"Neural Innervation of White Adipose Tissue and the Control of Lipolysis","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²¹","plainTextFormattedCitation":"121","previouslyFormattedCitation":"¹²¹"},"properties":{"noteIndex":0},"schema":""}121. Upon WAT SNS stimulation, vascular permeability is increased which allows liberated FFA to leave the interstitial space and remove the negative feedback on lipolysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.immuni.2010.12.017.Two-stage","ISBN":"6176321972","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shrestha","given":"Yogendra B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Neuroendocrinology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"note":"NULL","page":"473-493","title":"Neural Innervation of White Adipose Tissue and the Control of Lipolysis","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²¹","plainTextFormattedCitation":"121","previouslyFormattedCitation":"¹²¹"},"properties":{"noteIndex":0},"schema":""}121, which would translate to a measurable decrease in tissue fat content (i.e. MRI FF). Given that the posterior neck SAT is proximal to the interscapular region, which is where BAT is abundant and active in human infantsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}6, this fat pad might have an augmented capacity for NST under acute cold exposure compared to more distal subcutaneous depots, such as the abdomenADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/JP270805","ISSN":"1469-7793","PMID":"26096127","abstract":"KEY POINTS: White to brown adipose tissue conversion and thermogenesis can be ignited by different conditions or agents and its sustainability over the long term is still unclear. Browning of rat retroperitoneal white adipose tissue (rpWAT) during cold acclimation involves two temporally apparent components: (1) a predominant non-selective browning of most adipocytes and an initial sharp but transient induction of uncoupling protein 1, peroxisome proliferator-activated receptor (PPAR) coactivator-1α, PPARγ and PPARα expression, and (2) the subsistence of relatively few thermogenically competent adipocytes after 45 days of cold acclimation. The different behaviours of two rpWAT beige/brown adipocyte subsets control temporal aspects of the browning process, and thus regulation of both components may influence body weight and the potential successfulness of anti-obesity therapies. ABSTRACT: Conversion of white into brown adipose tissue may have important implications in obesity resistance and treatment. Several browning agents or conditions ignite thermogenesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in a brownish/burning mode over the long term, we investigated the progression of the rat retroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the early stages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularization and thermogenic-profile induction, as demonstrated by the presence of a multitude of uncoupling protein 1 (UCP1)-immunopositive paucilocular adipocytes containing peroxisome proliferator-activated receptor (PPAR) coactivator-1α (PGC-1α) and PR domain-containing 16 (PRDM16) in their nuclei. After 45 days, all adipocytes remained PRDM16 immunopositive, but only a few multilocular adipocytes rich in mitochondria remained UCP1/PGC-1α immunopositive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred following cold exposure, but returned to starting levels after cold acclimation. Compared with controls (22 ± 1 °C), levels of UCP1 mRNA increased in parallel with PPARγ (PPARα from days 1 to 7 and PGC-1α on day 1). Transcriptional recruitment of rpWAT was followed by an increase in UCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocytes within rpWAT underwent transient brown-fat-like thermogenic recruitment upon stimulation, but only a minority of cells retained a brown adipose tissue-like phenotype after the at…","author":[{"dropping-particle":"","family":"Jankovic","given":"Aleksandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Golic","given":"Igor","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markelic","given":"Milica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stancic","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Otasevic","given":"Vesna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buzadzic","given":"Biljana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korac","given":"Aleksandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korac","given":"Bato","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-1","issue":"15","issued":{"date-parts":[["2015"]]},"page":"3267-80","title":"Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation.","type":"article-journal","volume":"593"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²²","plainTextFormattedCitation":"122","previouslyFormattedCitation":"¹²²"},"properties":{"noteIndex":0},"schema":""}122. For instance, the range of pre-cold posterior neck SAT FF intersected with the range of pre-cold SCV BAT FF (66.9%-89.4% and 59.4%-75.6%, respectively) despite differences in thresholding techniques, suggesting that these two anatomically, and presumably functionally,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁵","plainTextFormattedCitation":"55","previouslyFormattedCitation":"⁵⁵"},"properties":{"noteIndex":0},"schema":""}55 distinct fat pads might not have unique MR signatures. In line with this notion, Jones et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.mri.2018.04.013","ISSN":"0730725X","author":[{"dropping-particle":"","family":"Jones","given":"Terence A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wayte","given":"Sarah C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reddy","given":"Narendra L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adesanya","given":"Oludolapo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitriadis","given":"George K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barber","given":"Thomas M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutchinson","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Imaging","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"61-68","publisher":"Elsevier","title":"Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps","type":"article-journal","volume":"51"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁹","plainTextFormattedCitation":"59","previouslyFormattedCitation":"⁵⁹"},"properties":{"noteIndex":0},"schema":""}59 recently attempted to identify an optimal FF threshold to differentiate between SCV BAT and posterior neck SAT, but could not specify a universal cut-off that exhibited high sensitivity and specificity. Finally, Koskensalo et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁵","plainTextFormattedCitation":"55","previouslyFormattedCitation":"⁵⁵"},"properties":{"noteIndex":0},"schema":""}55 used proton magnetic resonance spectroscopy (1H-MRS) to measure the FF of SAT within upper posterior thoracic region (i.e. posterior neck SAT) in 10 healthy subjects aged 25-45. Despite reporting significantly larger pre-cold FF values within SAT (mean±SD of 88.3±4.8%), which may in part be attributed to the technical differences between 1H-MRS and chemical-shift MRI, this group found a significant decrease in SAT FF after a 2-hour individualized cooling protocol (mean±SD of 83.9±6.6%)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁵","plainTextFormattedCitation":"55","previouslyFormattedCitation":"⁵⁵"},"properties":{"noteIndex":0},"schema":""}55. This was paralleled by an insignificant cold-induced change in SCV BAT FF, and researchers attributed their findings to increased lipolysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.molmet.2016.06.013","ISSN":"2212-8778","author":[{"dropping-particle":"","family":"Garretson","given":"John T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szymanski","given":"Laura A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwartz","given":"Gary J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Metabolism","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"626-634","publisher":"Elsevier GmbH","title":"Lipolysis sensation by white fat afferent nerves triggers brown fat thermogenesis","type":"article-journal","volume":"5"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁴","plainTextFormattedCitation":"94","previouslyFormattedCitation":"⁹⁴"},"properties":{"noteIndex":0},"schema":""}94 and perfusionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3557","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"27226402","abstract":"Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the beta3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 +/- 1 mm3 versus 65 +/- 3 mm3 ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Panagia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Y I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"H H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ernande","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sosnovik","given":"D E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR Biomed","id":"ITEM-1","issue":"October 2015","issued":{"date-parts":[["2016"]]},"page":"978-984","title":"Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁶","plainTextFormattedCitation":"106","previouslyFormattedCitation":"¹⁰⁶"},"properties":{"noteIndex":0},"schema":""}106 in the posterior neck SAT. These findings are substantiated by Muzik et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"doi:10.2967/jnumed.112.111336.","ISBN":"1535-5667 (Electronic)\\n0161-5505 (Linking)","ISSN":"1535-5667","PMID":"23362317","abstract":"UNLABELLED Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. METHODS Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. RESULTS The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40…","author":[{"dropping-particle":"","family":"Muzik","given":"Otto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangner","given":"Thomas J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"William R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Ajay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janisse","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013","4"]]},"note":"From Duplicate 2 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, Otto; Mangner, Thomas J; Leonard, William R; Kumar, Ajay; Janisse, James; Granneman, James G)\n\nFrom Duplicate 1 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, O; Manger, T; Leonard, WR; Kumar, A; Janisse, J; Granneman, JG)\n\nNULL","page":"523-531","publisher":"Society of Nuclear Medicine","title":"15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹¹","plainTextFormattedCitation":"91","previouslyFormattedCitation":"⁹¹"},"properties":{"noteIndex":0},"schema":""}91 who quantified lower tissue radiodensity (i.e. CT HU’s), higher glucose uptake, and a higher metabolic rate of oxygen in WAT proximal to the SCV region compared to the abdomen. Considering that a consensus has not been reached, future investigations should consider using larger cohorts and standardized approaches to cold stimulation and BAT detection in order to clarify the role of the posterior neck SAT within whole-body thermogenesis.Objective 2: Relationship between indices of BAT activity at time points of interest and covariates of BAT activity.In this study, moderate-to-strong associations between indices of body composition and BAT activity throughout the time course were identified (i.e. |rho|=0.393-0.964); consistent with our current understanding of BAT in humans. For example, Din et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-2698","ISSN":"1945-7197","PMID":"28368474","abstract":"Context Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, where computed tomography (CT) is commonly used as an anatomical reference for metabolic PET (positron emission tomography) imaging. However, the capacity of CT to provide metabolic information has been underexploited. Objective To evaluate whether CT radiodensity of BAT could non-invasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Further, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity. And, whether BAT can be differentiated from white adipose tissue (WAT) solely using CT based measurements. Design, Setting and Participants A cross-sectional study evaluating sixty-six healthy human subjects with CT, PET and 1H-magnetic resonance spectroscopy (1H-MRS). Main Outcome Measures BAT radiodensity was measured with CT. BAT stored triglyceride content was measured with 1H-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [15O]H2O, along with glucose or fatty acid uptake using [18F]FDG or [18F]FTHA PET imaging, respectively. Results BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both non-active BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters. Conclusion BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight in whole-body systemic metabolic health.","author":[{"dropping-particle":"","family":"Din","given":"Mueez U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kudomi","given":"Nobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solin","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of clinical endocrinology and metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Human brown fat radiodensity indicates underlying tissue composition and systemic metabolic health.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²³","plainTextFormattedCitation":"123","previouslyFormattedCitation":"¹²³"},"properties":{"noteIndex":0},"schema":""}123 investigated the SCV BAT of a heterogeneous study population (n=66, 45F/21M, 25-50 years, all BMI categories) using CT and found significant inverse relationships between measures of adiposity (i.e. BMI, waist circumference, and hip circumference) and cold-activated BAT radiodensity (i.e. HUs – an indirect surrogate of fat tissue content), which remained significant after adjustment for age (r=-0.71, -0.75, and -0.62, respectively). In recording MRI-derived FF before and after cooling (individualized protocol using a water-perfused blanket), Deng and colleages.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 found that male subjects under the age of 30 with a greater BMI and % body fat had a higher SCV FF at both time points (r>0.7 for all). However, this same studyADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38, among othersADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"doi:10.2967/jnumed.112.111336.","ISBN":"1535-5667 (Electronic)\\n0161-5505 (Linking)","ISSN":"1535-5667","PMID":"23362317","abstract":"UNLABELLED Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. METHODS Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. RESULTS The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40…","author":[{"dropping-particle":"","family":"Muzik","given":"Otto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangner","given":"Thomas J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"William R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Ajay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janisse","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013","4"]]},"note":"From Duplicate 2 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, Otto; Mangner, Thomas J; Leonard, William R; Kumar, Ajay; Janisse, James; Granneman, James G)\n\nFrom Duplicate 1 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, O; Manger, T; Leonard, WR; Kumar, A; Janisse, J; Granneman, JG)\n\nNULL","page":"523-531","publisher":"Society of Nuclear Medicine","title":"15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat","type":"article-journal","volume":"54"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"^55,63,91","plainTextFormattedCitation":"55,63,91","previouslyFormattedCitation":"^55,63,91"},"properties":{"noteIndex":0},"schema":""}55,63,91 reported no observed correlations between PET-derived BAT activity (i.e. 18F-FDG or 15O2 uptake (BAT oxidative metabolism)) and body composition, which might be attributed to the inherent technical limitations of this imaging modalityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2014"]]},"page":"103-113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁹","plainTextFormattedCitation":"49","previouslyFormattedCitation":"⁴⁹"},"properties":{"noteIndex":0},"schema":""}49. Further, since lean mass is associated with an increased basal metabolic rate which in turn alters the lower critical temperature at which cold-induced thermogenesis is activatedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jtherbio.2017.08.006","ISSN":"18790992","PMID":"29037389","abstract":"It is colloquially stated that body size plays a role in the human response to cold, but the magnitude and details of this interaction are unclear. To explore the inherent influence of body size on cold-exposed metabolism, we investigated the relation between body composition and resting metabolic rate in humans at thermoneutrality and during cooling within the nonshivering thermogenesis range. Body composition and resting energy expenditure were measured in 20 lean and 20 overweight men at thermoneutrality and during individualized cold exposure. Metabolic rates as a function of ambient temperature were investigated considering the variability in body mass and composition. We observed an inverse relationship between body size and the lower critical temperature (LCT), i.e. the threshold where thermoneutrality ends and cold activates thermogenesis. LCT was higher in lean than overweight subjects (22.1 ± 0.6 vs 19.5 ± 0.5 °C, p < 0.001). Below LCT, minimum conductance was identical between lean and overweight (100 ± 4 vs 97 ± 3 kcal/°C/day respectively, p = 0.45). Overweight individuals had higher basal metabolic rate (BMR) explained mostly by the higher lean mass, and lower cold-induced thermogenesis (CIT) per degree of cold exposure. Below thermoneutrality, energy expenditure did not scale to lean body mass. Overweight subjects had lower heat loss per body surface area (44.7 ± 1.3 vs 54.7 ± 2.3 kcal/°C/m2/day, p < 0.001). We conclude that larger body sizes possessed reduced LCT as explained by higher BMR related to more lean mass rather than a change in whole-body conductance. Thus, larger individuals with higher lean mass need to be exposed to colder temperatures to activate CIT, not because of increased insulation, but because of a higher basal heat generation. Our study suggests that the distinct effects of body size and composition on energy expenditure should be taken in account when exploring the metabolism of humans exposed to cold.","author":[{"dropping-particle":"","family":"Nahon","given":"Kimberly J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boon","given":"Mari?tte R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Doornink","given":"Fleur","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jazet","given":"Ingrid M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C.N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abreu-Vieira","given":"Gustavo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Thermal Biology","id":"ITEM-1","issue":"July","issued":{"date-parts":[["2017"]]},"page":"238-248","publisher":"Elsevier Ltd","title":"Lower critical temperature and cold-induced thermogenesis of lean and overweight humans are inversely related to body mass and basal metabolic rate","type":"article-journal","volume":"69"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²⁴","plainTextFormattedCitation":"124","previouslyFormattedCitation":"¹²⁴"},"properties":{"noteIndex":0},"schema":""}124, those with a higher LMI might not have been as “cold” as those with a comparatively low LMI. However, given that inlet-outlet temperature differences were comparable across the cohort, and that no associations between LMI and indices of BAT activity were observed (Figure 20 in Appendix Section 7.3.7), this participant characteristic was likely not implicated in the results of this study. Overall, our findings that individuals with a higher BMI and % body fat had a blunted BAT-specific response to cold are well supported.An interesting result of the present study was the strong inverse correlation between BMI and AUC at ten minutes following the onset of cold exposure, suggesting that those with a lower BMI had a greater magnitude of change in FF at this time point (rho=-0.786; Figure 8 above). To the best of my knowledge, Rachid et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ijo.2015.94","ISSN":"0307-0565","author":[{"dropping-particle":"","family":"Rachid","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodovalho","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Folli","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beltramini","given":"G C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morari","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amorim","given":"B J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pedro","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramalho","given":"A F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombassaro","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tincani","given":"AJ","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaim","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pareja","given":"JC","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geloneze","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"CD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cendes","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"MJA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velloso","given":"LA","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷³","plainTextFormattedCitation":"73","previouslyFormattedCitation":"⁷³"},"properties":{"noteIndex":0},"schema":""}73 offers the only other evidence of this proposed relationship in humans. This group used hypothalamic functional MRI to detect BAT activity, which assumes that BAT is regulated solely by hypothalamic-generated sympathetic signals. In summary, Figures 5A and D from this publication (Appendix Section 7.1) showed that lean compared to obese females (n=12 in each group) displayed heightened hypothalamic activity within 5 minutes of a 16°C cold exposure. Although this is in line with the present findings, correlation analysis revealed no association between BAT activity (as determined by 18F-FDG uptake) and hypothalamic responsiveness to cold and therefore these results should be interpreted with caution.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ijo.2015.94","ISSN":"0307-0565","author":[{"dropping-particle":"","family":"Rachid","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodovalho","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Folli","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beltramini","given":"G C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morari","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amorim","given":"B J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pedro","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramalho","given":"A F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombassaro","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tincani","given":"AJ","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaim","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pareja","given":"JC","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geloneze","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"CD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cendes","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"MJA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velloso","given":"LA","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷³","plainTextFormattedCitation":"73","previouslyFormattedCitation":"⁷³"},"properties":{"noteIndex":0},"schema":""}73 Nonetheless, the notion that obese versus lean individuals have a blunted BAT-specific response to cold can be reasoned by the fact that human SCV BAT exhibits characteristics of “beige” fat, an inducible form of WATADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/jmri.25594","ISSN":"10531807","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L.J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-3","issued":{"date-parts":[["2017"]]},"page":"1-8","title":"Relation between brown adipose tissue and measures of obesity and metabolic dysfunction in patients with cardiovascular disease","type":"article-journal"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1152/ajpregu.00021.2014","ISBN":"1522-1490 (Electronic)\\r0363-6119 (Linking)","ISSN":"0363-6119","PMID":"24871967","abstract":"The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A. J. J.","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"AJP: Regulatory, Integrative and Comparative Physiology","id":"ITEM-4","issue":"2","issued":{"date-parts":[["2014"]]},"page":"103-113","title":"Cold-activated brown adipose tissue in human adults: methodological issues","type":"article-journal","volume":"307"},"uris":[""]},{"id":"ITEM-5","itemData":{"DOI":"10.1016/j.beem.2016.08.003","ISSN":"1521690X","PMID":"27697214","author":[{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Best Practice & Research Clinical Endocrinology & Metabolism","id":"ITEM-5","issue":"4","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"537-547","publisher":"Elsevier Ltd","title":"Activation and recruitment of brown adipose tissue by cold exposure and food ingredients in humans","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"^{6,8,49,67,125}","plainTextFormattedCitation":"6,8,49,67,125","previouslyFormattedCitation":"^{6,8,49,67,125}"},"properties":{"noteIndex":0},"schema":""}6,8,49,67,125. As one accretes more body fat, SCV BAT loses its “brown” phenotype and undergoes a shift in functionality from energy expenditure to storage, ultimately blunting one's BAT-specific thermogenic machineryADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25594","ISSN":"10531807","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L.J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-8","title":"Relation between brown adipose tissue and measures of obesity and metabolic dysfunction in patients with cardiovascular disease","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1210/jc.2012-1289","author":[{"dropping-particle":"","family":"Vijgen","given":"G H E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bouvy","given":"N D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teule","given":"G J J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-2","issue":"7","issued":{"date-parts":[["2012"]]},"page":"1229-1233","title":"Increase in Brown Adipose Tissue Activity after Weight Loss in Morbidly Obese Subjects","type":"article-journal","volume":"97"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1194/jlr.M079665","author":[{"dropping-particle":"","family":"Kotzbeck","given":"Petra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giordano","given":"Antonio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mondini","given":"Eleonora","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murano","given":"Incoronata","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Severi","given":"Ilenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Venema","given":"Wiebe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cecchini","given":"Maria Paola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cinti","given":"Saverio","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Lipid Research","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2018"]]},"page":"1-37","title":"Brown adipose tissue whitening leads to brown adipocyte death and adipose tissue inflammation","type":"article-journal"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1038/s41598-017-16463-6","author":[{"dropping-particle":"","family":"Alcalá","given":"Martín","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calderon-Dominguez","given":"María","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bustos","given":"Eduviges","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"Pilar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Casals","given":"Núria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Serra","given":"Dolors","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viana","given":"Marta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herrero","given":"Laura","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-4","issue":"8","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"Increased inflammation , oxidative stress and mitochondrial respiration in brown adipose tissue from obese mice","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"^90,92,93,125","plainTextFormattedCitation":"90,92,93,125","previouslyFormattedCitation":"^90,92,93,125"},"properties":{"noteIndex":0},"schema":""}90,92,93,125. Furthermore, in addition to impairing whole-body insulin sensitivity, increasing adiposity also reduces the sympathetic drive and overall catabolic activity of SAT depotsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.immuni.2010.12.017.Two-stage","ISBN":"6176321972","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Bartness","given":"Timothy J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Liu","given":"Yang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shrestha","given":"Yogendra B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ryu","given":"Vitaly","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Neuroendocrinology","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2014"]]},"note":"NULL","page":"473-493","title":"Neural Innervation of White Adipose Tissue and the Control of Lipolysis","type":"article-journal","volume":"35"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2015.09.007","ISBN":"1932-7420 (Electronic)\r1550-4131 (Linking)","ISSN":"19327420","PMID":"26445512","abstract":"Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.","author":[{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2015"]]},"page":"546-559","publisher":"Elsevier Inc.","title":"Brown and beige fat: Physiological roles beyond heat generation","type":"article-journal","volume":"22"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-3","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"^12,20,121","plainTextFormattedCitation":"12,20,121","previouslyFormattedCitation":"^12,20,121"},"properties":{"noteIndex":0},"schema":""}12,20,121, thereby adversely impacting the utilization of glucose and FFA as exogenous fuels for NST. Despite this phenotype, Schreiber et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sedej","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-763.e7","publisher":"Elsevier Inc.","title":"Cold-Induced Thermogenesis Depends on ATGL- Mediated Lipolysis in Cardiac Muscle, but Not Brown","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁸","plainTextFormattedCitation":"118","previouslyFormattedCitation":"¹¹⁸"},"properties":{"noteIndex":0},"schema":""}118 observed sustained UCP1 protein content and mitochondrial function in a lipolysis-deficient mouse model with induced whitening of BAT. This suggests that upon continued activation by a stimulus, such as cold, the thermogenic response in BAT tissue can be rescuedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1113/JP270805","ISSN":"1469-7793","PMID":"26096127","abstract":"KEY POINTS: White to brown adipose tissue conversion and thermogenesis can be ignited by different conditions or agents and its sustainability over the long term is still unclear. Browning of rat retroperitoneal white adipose tissue (rpWAT) during cold acclimation involves two temporally apparent components: (1) a predominant non-selective browning of most adipocytes and an initial sharp but transient induction of uncoupling protein 1, peroxisome proliferator-activated receptor (PPAR) coactivator-1α, PPARγ and PPARα expression, and (2) the subsistence of relatively few thermogenically competent adipocytes after 45 days of cold acclimation. The different behaviours of two rpWAT beige/brown adipocyte subsets control temporal aspects of the browning process, and thus regulation of both components may influence body weight and the potential successfulness of anti-obesity therapies. ABSTRACT: Conversion of white into brown adipose tissue may have important implications in obesity resistance and treatment. Several browning agents or conditions ignite thermogenesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in a brownish/burning mode over the long term, we investigated the progression of the rat retroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the early stages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularization and thermogenic-profile induction, as demonstrated by the presence of a multitude of uncoupling protein 1 (UCP1)-immunopositive paucilocular adipocytes containing peroxisome proliferator-activated receptor (PPAR) coactivator-1α (PGC-1α) and PR domain-containing 16 (PRDM16) in their nuclei. After 45 days, all adipocytes remained PRDM16 immunopositive, but only a few multilocular adipocytes rich in mitochondria remained UCP1/PGC-1α immunopositive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred following cold exposure, but returned to starting levels after cold acclimation. Compared with controls (22 ± 1 °C), levels of UCP1 mRNA increased in parallel with PPARγ (PPARα from days 1 to 7 and PGC-1α on day 1). Transcriptional recruitment of rpWAT was followed by an increase in UCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocytes within rpWAT underwent transient brown-fat-like thermogenic recruitment upon stimulation, but only a minority of cells retained a brown adipose tissue-like phenotype after the at…","author":[{"dropping-particle":"","family":"Jankovic","given":"Aleksandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Golic","given":"Igor","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Markelic","given":"Milica","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stancic","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Otasevic","given":"Vesna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buzadzic","given":"Biljana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korac","given":"Aleksandra","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Korac","given":"Bato","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-2","issue":"15","issued":{"date-parts":[["2015"]]},"page":"3267-80","title":"Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation.","type":"article-journal","volume":"593"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.cmet.2018.03.005","ISSN":"19327420","PMID":"29657031","abstract":"Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological “whitening,” but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals. Both beige and brown adipocytes “whiten” upon warming. Roh et al. elegantly show that beige, but not brown, adipocytes undergo temperature-dependent reprogramming between brown- and white-like states, while retaining epigenomic memory of prior cold exposure. A transcriptional cascade underlies this plasticity response to environmental signals.","author":[{"dropping-particle":"","family":"Roh","given":"Hyun Cheol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsai","given":"Linus T.Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Mengle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tenen","given":"Danielle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Yachen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumari","given":"Manju","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lyubetskaya","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobs","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dawes","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"Rana K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosen","given":"Evan D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2018"]]},"page":"1121-1137","publisher":"Elsevier Inc.","title":"Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"^6,122,126","plainTextFormattedCitation":"6,122,126","previouslyFormattedCitation":"^6,122,126"},"properties":{"noteIndex":0},"schema":""}6,122,126. As such, a smaller magnitude of change in FF among those with a higher BMI/% body fat as compared to leaner individuals can be partially explained by the beige nature of SCV BAT. In other words, a “whiter” BAT might have a reduced capacity for NST during acute exposures and might in fact take longer to “wake up” before the thermogenic machinery becomes fully active. This concept also alludes to one’s a priori state of BAT activation, which ties into the succeeding discussion section.Other participant characteristics that could implicate BAT activityThere are many factors that can influence an individual’s BAT-specific response to cold exposure, and one’s a priori acclimation state is a notable predictor. Various independent research groups have examined the effects of cold acclimation on BAT activity in healthy human cohorts. Seminal investigations have observed heightened 18F-FDG uptake by BAT in subjects studied in the winter versus the summer monthsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s00247-010-1925-y","ISBN":"1432-1998 (Electronic)\\n0301-0449 (Linking)","ISSN":"03010449","PMID":"21161205","abstract":"Positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose (FDG) fused with CT ((18)F-FDG PET/CT) has been widely adopted in oncological imaging. However, it is known that benign lesions and other metabolically active tissues, such as brown adipose tissue (BAT), can accumulate (18)F-FDG, potentially resulting in false-positive interpretation. Previous studies have reported that (18)F-FDG uptake in BAT is more common in children than in adults. We illustrate BAT FDG uptake in various anatomical locations in children and adolescents. We also review what is known about the effects of patient-related physical attributes and environmental temperatures on BAT FDG uptake, and discuss methods used to reduce BAT FDG uptake on (18)F-FDG PET.","author":[{"dropping-particle":"","family":"Hong","given":"Terence S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shammas","given":"Amer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Charron","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zukotynski","given":"Katherine A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drubach","given":"Laura A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lim","given":"Ruth","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric Radiology","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2011"]]},"page":"759-768","title":"Brown adipose tissue 18F-FDG uptake in pediatric PET/CT imaging","type":"article-journal","volume":"41"},"uris":[""]},{"id":"ITEM-2","itemData":{"author":[{"dropping-particle":"","family":"Huttunen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hirvonen","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinnula","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Eur J Appl Physiol Occup Physiol","id":"ITEM-2","issue":"4","issued":{"date-parts":[["1981"]]},"page":"339-345","title":"The occurence of brown adipose tissue in outdoor workers","type":"article-journal","volume":"46"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1007/s00259-007-0670-4","ISBN":"0025900706","ISSN":"16197070","PMID":"18157529","abstract":"OBJECTIVES: It has been reported that the prevalence of (18)F fluorodeoxyglucose (FDG) uptake in brown adipose tissue (BAT) is related to outdoor temperature, i.e., more frequent during the colder periods of the year. The purpose of this study was to assess the temporal relationship between BAT FDG uptake and temperature. We correlated the prevalence of BAT with average temperatures (divided into five temperature ranges) of seven different durations.\\n\\nMETHODS: One thousand four hundred ninety-five consecutive FDG Positron emission tomography (PET) studies in 1,159 patients (566 male and 593 female, mean age = 60.4 years) were retrospectively reviewed. FDG uptake with distinct patterns compatible with BAT was identified by a consensus of two readers. The local daily average temperature from January 2000 to November 2003 (beginning 60 days before the date of first PET scan) were obtained, and 2-, 3-, 7-, 14-, 30-, and 60-day average temperatures before the date of a PET study were calculated. The prevalence of BAT FDG uptake was correlated with these various average temperatures.\\n\\nRESULTS: The daily, 2-day, 3-day, and 7-day average temperature had an inverse relation with the prevalence of BAT, i.e., the lower the temperature, the higher prevalence of BAT. When the temperature was averaged over 14 days or longer, this inverse relationship between the temperature and the prevalence of BAT was no longer preserved.\\n\\nCONCLUSIONS: Our data suggest that increased FDG uptake in BAT occurs more often as an acute response to cold weather (1-7 days) rather than to prolonged periods of average cold weather.","author":[{"dropping-particle":"","family":"Kim","given":"Sunhee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krynyckyi","given":"Borys R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Machac","given":"Josef","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kim","given":"Chun K.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Journal of Nuclear Medicine and Molecular Imaging","id":"ITEM-3","issue":"5","issued":{"date-parts":[["2008"]]},"page":"984-989","title":"Temporal relation between temperature change and FDG uptake in brown adipose tissue","type":"article-journal","volume":"35"},"uris":[""]}],"mendeley":{"formattedCitation":"^4,127,128","plainTextFormattedCitation":"4,127,128","previouslyFormattedCitation":"^4,127,128"},"properties":{"noteIndex":0},"schema":""}4,127,128. In addition, Lee et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db14-0513","author":[{"dropping-particle":"","family":"Lee","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Sheila","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Linderman","given":"Joyce","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Courville","given":"Amber B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brychta","given":"Robert J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dieckmann","given":"W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werner","given":"CD.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"KY.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Celi","given":"FS.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"page":"3686-3698","title":"Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans","type":"article-journal","volume":"63"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²⁹","plainTextFormattedCitation":"129","previouslyFormattedCitation":"¹²⁹"},"properties":{"noteIndex":0},"schema":""}129 examined the effects of a 4-month crossover study (24°C 19°C 24°C 27°C) of overnight temperature acclimation on five healthy men and found increased BAT activity (i.e. augmented 18F-FDG uptake and radiodensity) after the cold month, which was muted after subsequent warm exposures. This early knowledge shed light on the notion that BAT activity is facultative, as it is only functional when acutely activatedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60941","ISBN":"1558-8238 (Electronic)\\n0021-9738 (Linking)","ISSN":"00219738","PMID":"22269320","abstract":"That adult humans possess brown fat is now accepted - but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity - provided that brown fat becomes activated not only by cold but also through food-related stimuli.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"486-489","title":"Yes, even human brown fat is on fire!","type":"article-journal","volume":"122"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2018.03.005","ISSN":"19327420","PMID":"29657031","abstract":"Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological “whitening,” but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure. We further show that a transcriptional cascade involving glucocorticoid receptor and Zfp423 can drive warm-induced whitening of beige adipocytes. These studies identify the epigenomic and transcriptional bases of an extraordinary example of cellular plasticity in response to environmental signals. Both beige and brown adipocytes “whiten” upon warming. Roh et al. elegantly show that beige, but not brown, adipocytes undergo temperature-dependent reprogramming between brown- and white-like states, while retaining epigenomic memory of prior cold exposure. A transcriptional cascade underlies this plasticity response to environmental signals.","author":[{"dropping-particle":"","family":"Roh","given":"Hyun Cheol","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsai","given":"Linus T.Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Mengle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tenen","given":"Danielle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Yachen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumari","given":"Manju","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lyubetskaya","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobs","given":"Christopher","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dawes","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"Rana K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosen","given":"Evan D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2018"]]},"page":"1121-1137","publisher":"Elsevier Inc.","title":"Warming Induces Significant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity","type":"article-journal","volume":"27"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/j.mri.2018.04.013","ISSN":"0730725X","author":[{"dropping-particle":"","family":"Jones","given":"Terence A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wayte","given":"Sarah C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reddy","given":"Narendra L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adesanya","given":"Oludolapo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitriadis","given":"George K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Barber","given":"Thomas M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hutchinson","given":"Charles E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Imaging","id":"ITEM-3","issue":"3","issued":{"date-parts":[["2018"]]},"page":"61-68","publisher":"Elsevier","title":"Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps","type":"article-journal","volume":"51"},"uris":[""]}],"mendeley":{"formattedCitation":"^59,113,126","plainTextFormattedCitation":"59,113,126","previouslyFormattedCitation":"^59,113,126"},"properties":{"noteIndex":0},"schema":""}59,113,126. A few research groups have since recruited small, homogenous, samples of human subjects and measured clinical and BAT-specific outcomes before and after a cold acclimation protocol of several weeks in durationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ncomms14146","ISSN":"2041-1723","PMID":"28134339","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans 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Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.","author":[{"dropping-particle":"","family":"Hanssen","given":"Mark J W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"Van Der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jardon","given":"Kelly M C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaart","given":"Gert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"Van","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-5","issue":"5","issued":{"date-parts":[["2016"]]},"page":"1179-1189","title":"Short-term cold acclimation recruits brown adipose tissue in obese humans","type":"article-journal","volume":"65"},"uris":[""]},{"id":"ITEM-6","itemData":{"DOI":"10.1172/JCI68993.dence","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vijgen","given":"Guy H E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Mari?lle G W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hansen","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?rgensen","given":"Johanna A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D Van Marken","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Investgation","id":"ITEM-6","issue":"8","issued":{"date-parts":[["2013"]]},"page":"3395-3403","title":"Cold acclimation recruits human brown fat and increases nonshivering thermogenesis","type":"article-journal","volume":"123"},"uris":[""]}],"mendeley":{"formattedCitation":"^{8,10,89,104,114,130}","plainTextFormattedCitation":"8,10,89,104,114,130","previouslyFormattedCitation":"^{8,10,89,104,114,130}"},"properties":{"noteIndex":0},"schema":""}8,10,89,104,114,130. Van der Lans et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI68993.dence","author":[{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vijgen","given":"Guy H E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visser","given":"Mari?lle G W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vosselman","given":"Maarten J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hansen","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"J?rgensen","given":"Johanna A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D Van Marken","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Investgation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2013"]]},"page":"3395-3403","title":"Cold acclimation recruits human brown fat and increases nonshivering thermogenesis","type":"article-journal","volume":"123"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³⁰","plainTextFormattedCitation":"130","previouslyFormattedCitation":"¹³⁰"},"properties":{"noteIndex":0},"schema":""}130 exposed a group of lean adults under the age of 30 to an ambient temperature of 15-16°C for 2-6 hours on 10 consecutive days and reported increased 18F-FDG uptake and whole-body EE in parallel with decreased self-reported shivering. Hanssen et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/nm.3891","author":[{"dropping-particle":"","family":"Hanssen","given":"Mark J W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk a J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaart","given":"Gert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Driessche","given":"JJ","non-dropping-particle":"van den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jorgensen","given":"Johanna A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Boekschoten","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hesselink","given":"Matthijs K C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Havekes","given":"Louis M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersten","given":"Sander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Medicine","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2015"]]},"page":"6-10","title":"Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus.","type":"article-journal","volume":"21"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2337/db15-1372","ISSN":"1939327X","PMID":"26718499","abstract":"Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.","author":[{"dropping-particle":"","family":"Hanssen","given":"Mark J W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"Van Der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jardon","given":"Kelly M C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schaart","given":"Gert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"Van","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2016"]]},"page":"1179-1189","title":"Short-term cold acclimation recruits brown adipose tissue in obese humans","type":"article-journal","volume":"65"},"uris":[""]}],"mendeley":{"formattedCitation":"^10,104","plainTextFormattedCitation":"10,104","previouslyFormattedCitation":"^10,104"},"properties":{"noteIndex":0},"schema":""}10,104 used the same acclimation protocol to repeat these findings in overweight/obese populations. Similarly, Blondin et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ncomms14146","ISSN":"2041-1723","PMID":"28134339","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"14146","title":"Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁴","plainTextFormattedCitation":"114","previouslyFormattedCitation":"¹¹⁴"},"properties":{"noteIndex":0},"schema":""}114 studied the effects of a four-week (3 hours at 18°C, five times per week) cold sensitization in a homogenous population of lean males and indicated a 2.6-fold increase in BAT-oxidative metabolism without alterations in objectively measured shivering intensity. These results were furthered by Yoneshiro et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI67803DS1","author":[{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aita","given":"Sayuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kayahara","given":"Takashi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Iwanaga","given":"Toshihiko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Investgation","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2013"]]},"page":"3404-3408","title":"Recruited brown adipose tissue as an antiobesity agent in humans","type":"article-journal","volume":"123"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁹","plainTextFormattedCitation":"89","previouslyFormattedCitation":"⁸⁹"},"properties":{"noteIndex":0},"schema":""}89 who subjected 12 males to 2 hours of 17°C daily for 6 weeks and observed heightened BAT recruitment, increased EE, and decreased % body fat even among those with unobserved 18F-FDG uptake at baseline. Therefore, the frequency and intensity of exposure to cold environments could certainly be implicated in one’s time course of change in SCV BAT FF. Although we saw no influence of outdoor temperature on MRI findings (Figure 17 in Appendix Section 7.3.7), we did not control the extent to which subjects were exposed to their ambient environment (e.g. being outside and wearing a jacket of a certain thermal insulation value) and therefore numerous external factors likely confounded this relationship.Individual variation in cold-induced BAT activity could also be explained by differences in cardiac output, which would presumably enhance substrate delivery and subsequent distribution of generated heatADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-2698","ISSN":"1945-7197","PMID":"28368474","abstract":"Context Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, where computed tomography (CT) is commonly used as an anatomical reference for metabolic PET (positron emission tomography) imaging. However, the capacity of CT to provide metabolic information has been underexploited. Objective To evaluate whether CT radiodensity of BAT could non-invasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Further, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity. And, whether BAT can be differentiated from white adipose tissue (WAT) solely using CT based measurements. Design, Setting and Participants A cross-sectional study evaluating sixty-six healthy human subjects with CT, PET and 1H-magnetic resonance spectroscopy (1H-MRS). Main Outcome Measures BAT radiodensity was measured with CT. BAT stored triglyceride content was measured with 1H-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [15O]H2O, along with glucose or fatty acid uptake using [18F]FDG or [18F]FTHA PET imaging, respectively. Results BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both non-active BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters. Conclusion BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight in whole-body systemic metabolic health.","author":[{"dropping-particle":"","family":"Din","given":"Mueez U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kudomi","given":"Nobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solin","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of clinical endocrinology and metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Human brown fat radiodensity indicates underlying tissue composition and systemic metabolic health.","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sedej","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-763.e7","publisher":"Elsevier Inc.","title":"Cold-Induced Thermogenesis Depends on ATGL- Mediated Lipolysis in Cardiac Muscle, but Not Brown","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"^118,123","plainTextFormattedCitation":"118,123","previouslyFormattedCitation":"^118,123"},"properties":{"noteIndex":0},"schema":""}118,123. Din et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-2698","ISSN":"1945-7197","PMID":"28368474","abstract":"Context Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, where computed tomography (CT) is commonly used as an anatomical reference for metabolic PET (positron emission tomography) imaging. However, the capacity of CT to provide metabolic information has been underexploited. Objective To evaluate whether CT radiodensity of BAT could non-invasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Further, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity. And, whether BAT can be differentiated from white adipose tissue (WAT) solely using CT based measurements. Design, Setting and Participants A cross-sectional study evaluating sixty-six healthy human subjects with CT, PET and 1H-magnetic resonance spectroscopy (1H-MRS). Main Outcome Measures BAT radiodensity was measured with CT. BAT stored triglyceride content was measured with 1H-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [15O]H2O, along with glucose or fatty acid uptake using [18F]FDG or [18F]FTHA PET imaging, respectively. Results BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both non-active BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters. Conclusion BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight in whole-body systemic metabolic health.","author":[{"dropping-particle":"","family":"Din","given":"Mueez U","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kudomi","given":"Nobu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Solin","given":"Olof","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of clinical endocrinology and metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Human brown fat radiodensity indicates underlying tissue composition and systemic metabolic health.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²³","plainTextFormattedCitation":"123","previouslyFormattedCitation":"¹²³"},"properties":{"noteIndex":0},"schema":""}123 correlated cold-induced BAT radiodensity (i.e. TAG use) with local blood volume, and Schreiber et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sedej","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-763.e7","publisher":"Elsevier Inc.","title":"Cold-Induced Thermogenesis Depends on ATGL- Mediated Lipolysis in Cardiac Muscle, but Not Brown","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁸","plainTextFormattedCitation":"118","previouslyFormattedCitation":"¹¹⁸"},"properties":{"noteIndex":0},"schema":""}118 suggested that impaired cardiac reserve contributes to cold intolerance in mice with defective BAT machinery. Although Flynn et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.echo.2015.06.014","ISBN":"1097-6795 (Electronic)\\r0894-7317 (Linking)","ISSN":"10976795","PMID":"26255029","abstract":"Background Brown adipose tissue (BAT) consumes glucose when it is activated by cold exposure, allowing its detection in humans by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT). The investigators recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). Here, they report the application of this method in healthy humans. Methods Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (??) of microbubble replenishment curves. All underwent 18F-FDG PET/CT after cold exposure. Results An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by 18F-FDG PET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median A?? = 3.3 AU/s [interquartile range, 0.5-5.7 AU/s] vs 1.25 AU/s [interquartile range, 0.5-2.6 AU/s]; P =.02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by 18F-FDG PET/CT (median maximal standardized uptake value, 2.25 [interquartile range, 1.53-4.57] vs 0.51 [interquartile range, 0.47-0.73]; P =.02). Conclusions The present study demonstrates the feasibility of using CEUS as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies.","author":[{"dropping-particle":"","family":"Flynn","given":"Aidan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Qian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Panagia","given":"Marcello","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdelbaky","given":"Amr","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Macnabb","given":"Megan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samir","given":"Anthony","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weyman","given":"Arthur E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tawakol","given":"Ahmed","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"Marielle","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the American Society of Echocardiography","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1247-1254","publisher":"Elsevier Inc","title":"Contrast-Enhanced Ultrasound: A Novel Noninvasive, Nonionizing Method for the Detection of Brown Adipose Tissue in Humans","type":"article-journal","volume":"28"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁸","plainTextFormattedCitation":"108","previouslyFormattedCitation":"¹⁰⁸"},"properties":{"noteIndex":0},"schema":""}108 disconnected BAT blood flow with total cardiac output, they were trialing a novel modality for BAT detection (i.e. contrast-enhanced ultrasound) and therefore this notion warrants further investigation.In summary, this study did not account for various factors that could influence MRI measures of BAT activity. Nonetheless, the goal of this project was not to identify the physiology behind cold tolerance but rather to present and identify potential predictors of the time course of change in FF during cooling.AUC as an indicator of BAT ActivityWe elected to use both FF reduction from baseline, a common MRI-derived indicator of BAT activity which describes a change in lipid fat content between two points, and AUC from baseline, which accounts for all measurements between two points to derive a magnitude of change over a defined time interval. As depicted by Figure 20 in Appendix Section 7.3.7, associations between AUC and indices of body composition were less variable than those produced by FF reduction, and ultimately did not change beyond 90 minutes of cooling. Further, the combination of AUC and BMI consistently produced moderate-to-strong Spearman correlation coefficients at each point over the time course of cooling. Therefore, this exploratory analysis substantiates earlier findings in that associations with established covariates of BAT activity can be detected soon after the onset of a cold stimulus, and also alludes to the potential utility of AUC as an indicator of BAT activity when more than two cold-induced measurements are obtained.Objective 3: Time course of FF during warmingIt was hypothesized that upon cessation of a sympathetic stimulus (i.e. BAT deactivation), FF would begin to recover towards baselineADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ncomms14146","ISSN":"2041-1723","PMID":"28134339","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"14146","title":"Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁴","plainTextFormattedCitation":"114","previouslyFormattedCitation":"¹¹⁴"},"properties":{"noteIndex":0},"schema":""}114. In line with this presumption, a recent report by Weir et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2018.04.020","ISSN":"19327420","abstract":"Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (～25°C) and cold exposure (～17°C), and blood flow was measured by133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate. Weir et al., using microdialysis, have shown that human brown adipose tissue (BAT) is metabolically active in warm conditions, with higher glucose uptake and lactate release than white AT. Cold activation increased glucose and glutamate uptake and glycerol release by BAT, quantifying substrate utilization and hydrolysis of BAT triglycerides during thermogenesis.","author":[{"dropping-particle":"","family":"Weir","given":"Graeme","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramage","given":"Lynne E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Akyol","given":"Murat","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rhodes","given":"Jonathan K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kyle","given":"Catriona J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fletcher","given":"Alison M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Craven","given":"Thomas H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wakelin","given":"Sonia J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Drake","given":"Amanda J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gregoriades","given":"Maria Lena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ashton","given":"Ceri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weir","given":"Nick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beek","given":"Edwin J.R.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karpe","given":"Fredrik","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Brian R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stimson","given":"Roland H.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"1-8","publisher":"Elsevier Inc.","title":"Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³¹","plainTextFormattedCitation":"131","previouslyFormattedCitation":"¹³¹"},"properties":{"noteIndex":0},"schema":""}131 indicated persistent 18F-FDG uptake by SCV BAT during warming (ambient temperature of ~25°C), but that much of this internalized glucose is used for de novo lipogenesis. However, as presented in Figure 9 above, FF was maintained at or around the last measured cold-induced value in the current study.Four independent groups have measured SCV FF in both cooling to warming conditionsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-3","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-4","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^38,55,56,58","plainTextFormattedCitation":"38,55,56,58","previouslyFormattedCitation":"^38,55,56,58"},"properties":{"noteIndex":0},"schema":""}38,55,56,58. Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 implemented a similar warming phase of 30 minutes at 37°C and reported comparable subject-specific patterns of change in FF reduction despite notable differences in methodologies. According to Figure 4 in this publication (Appendix Section 7.1), warming induced a mild increase in iBAT FF in one subject, a continuing decrease in five subjects, and no change in the remaining fourADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56. Considered together, the five female participants had a net slope of -1.9±11.8%/hour and the five males had a net slope of -0.9±4.4%/hour, indicating a slight decrease in iBAT FF during warmingADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56. Though not a time course representation, Deng et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38 obtained MRI scans following 60-minutes of individualized cooling and 20-minutes of warming (30°C) in 15 young male participants. Their descriptive analysis indicated variability in the direction and degree of FF changes during the latter phase, as seven subjects showed a trend of recovery towards baseline, and six had continued decreasesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38. They also provided the following group-wise summary to show a lack of change in FF after transitioning from cold to warm conditions: FF of normal/overweight males during cooling = 67±8% and warming = 67±9%; FF of obese males during cooling = 84±4%, warm = 83±4%ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38. However, warming appeared to restore R2* (inverse of T2*) to pre-cold levels in the majority of participantsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25836","author":[{"dropping-particle":"","family":"Deng","given":"Jie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neff","given":"Lisa M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rubert","given":"Nicholas C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Bin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shore","given":"Richard M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Samet","given":"Jonathan D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nelson","given":"Paige C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Landsberg","given":"Lewis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"MRI Characterization of Brown Adipose Tissue Under Thermal Challenges in Normal Weight, Overweight, and Obese Young Men","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³⁸","plainTextFormattedCitation":"38","previouslyFormattedCitation":"³⁸"},"properties":{"noteIndex":0},"schema":""}38. Lundstrom and colleaguesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0126705","ISSN":"19326203","PMID":"25928226","abstract":"OBJECTIVES: To evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.\\n\\nMATERIALS AND METHODS: Nine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).\\n\\nRESULTS: sBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).\\n\\nCONCLUSIONS: The sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johansson","given":"Lars","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"1-13","title":"Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁸","plainTextFormattedCitation":"58","previouslyFormattedCitation":"⁵⁸"},"properties":{"noteIndex":0},"schema":""}58 mirrored this finding (i.e. BAT FF remained decreased at the post-cooling level (-1.92%), whereas R2* showed a weak trend towards normalization) in a similar population of subjects, which might imply that reheating has a greater impact on lowering perfusion in the BAT tissue. Though not a primary outcome of the present study, changes in T2* (i.e. indirect surrogate of tissue perfusion) were measured alongside FF and Figure 21 in Appendix Section 7.3.8 appears to show no influence of warming on the trajectory of T2*. Given that FF also remains stable during this phase, a balance between lipid consumption and oxidation must persist in order to maintain the relative amounts of fat and water in this tissue. The findings from the present study are corroborated by a recent report which indicated persistent, albeit significantly reduced, 18F-FDG uptake in SCV BAT after 180 minutes of 23°C warming which immediately succeeded 120 minutes of ~14°C coolingADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"","ISSN":"0012-1797","PMID":"29795459","author":[{"dropping-particle":"","family":"Leitner","given":"Brooks P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weiner","given":"L S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Desir","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sze","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Selen","given":"D J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsang","given":"Cathy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"G M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"A M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issued":{"date-parts":[["2018"]]},"page":"A550","publisher":"Springer US","title":"Kinetics of human brown adipose tissue activation and deactivation","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰²","plainTextFormattedCitation":"102","previouslyFormattedCitation":"¹⁰²"},"properties":{"noteIndex":0},"schema":""}102. In contrast to above, Koskensalo et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1210/jc.2016-3086","ISSN":"0021-972X","author":[{"dropping-particle":"","family":"Koskensalo","given":"Kalle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raiko","given":"Juho","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saari","given":"Teemu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Virva","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eskola","given":"Olli","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nuutila","given":"Pirjo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunavaara","given":"Jani","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Parkkola","given":"Riitta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Clinical Endocrinology & Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2017"]]},"page":"1200-1207","title":"Human Brown Adipose Tissue Temperature and Fat Fraction Are Related to Its Metabolic Activity","type":"article-journal","volume":"102"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁵","plainTextFormattedCitation":"55","previouslyFormattedCitation":"⁵⁵"},"properties":{"noteIndex":0},"schema":""}55 reported a significantly lower 1H-MRS-derived BAT FF in cold (2 hours at individualized temperature) compared to warm (not specified) conditions (76.0±5.6% and 80.9±5.6, respectively) in a small, heterogeneous sample of 10 healthy adults. However, these results are controversial given that measurements were obtained on separate days. Taken together, these data demonstrate that human SCV BAT activity may persist for an extended period after removal of a sympathetic stimulus, such as cold exposure.Although underwhelming, the findings that FF is not influenced by warming suggests that an increase in temperature prior to post-cooling MRI scans would not mask the changes in FF but could instead be used as a standardized methodological tool for limiting the prevalence of motion artifacts due to shivering. Furthermore, a brief time lag between the cessation of cooling and acquisition of SCV BAT FF scans, as often reported in studies performing a cold exposure outside of an MRI, would not impact cold-stimulated measures. Therefore, regardless of the outcome, this investigation was highly warranted.CONCLUSIONSummary of FindingsIn this study, we quantified SCV BAT FF during cooling (3 hours at 18°C) and warming (30 minutes at 32°C) and concluded the following: (i) the cold-induced reductions in SCV BAT FF were rapid and transient, as a significant reduction in FF was detected as soon as 10 minutes following the onset of cold exposure (mean difference = -1.6%; p=0.005), and changes in FF beyond 30 minutes of cooling were similar to those measured after three hours (p<0.05); ii) the posterior neck SAT did not experience significant cold-induced changes in FF; iii) although every participant had a measurable decline in FF, those with a higher BMI and % body fat had a smaller magnitude of change throughout the time course; and iv) warming did not appear to influence the trajectory of SCV BAT FF. These findings reinforce the feasibility of implementing a mild cold exposure protocol of a short duration to capture changes in MRI measures of SCV BAT in humans.Limitations and Recommendations for Future StudiesThis study has notable limitations. First, only twelve subjects were included in the present analysis, and seven were able to complete the full duration of cold exposure while inside the MRI. Though potential covariates of BAT activity such as ageADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.115.165829","ISSN":"1535-5667","PMID":"26609175","abstract":"Brown adipose tissue (BAT) could facilitate weight loss by increasing energy expenditure. Cold is a potent stimulator of BAT, activating BAT primarily through the sympathetic nervous system (SNS). Older or overweight individuals have less metabolic BAT activity than the lean and young, but the role of the SNS in this decline is unknown. We aimed to determine whether this lower metabolic BAT activity in older or overweight individuals can be explained by a lower SNS response to cold.\\n\\nMETHODS: This was a prospective observational study. We included 10 young obese, 11 old lean and 14 young lean healthy males. All subjects underwent a (18)F-Fluorodeoxyglucose ((18)F-FDG) PET-CT and a (123)I-meta-iodobenzylguanidine ((123)I-mIBG) SPECT-CT after an overnight fast and two hours of cold exposure. Metabolic BAT activity was expressed as volume and as maximal standardised uptake value (SUVmax) of (18)F-FDG. BAT SNS activity was expressed as volume and as the ratio between (123)I-mIBG uptake in BAT and a reference region (SQUVmax of (123)I-mIBG).\\n\\nRESULTS: SUVmax, BAT volume and SQUVmax were significantly different between young and old (SUVmax 7.9[4.2-17.3] vs. 2.9[0.0-4.0], volume 124.8[10.9-338.8] vs 3.4 [0.0-10.9] and SQUVmax 2.7[1.9-4.7] vs 0.0[0.0-2.2] all p<0.01) but not between lean and obese (SUVmax 7.9[4.2-17.3] vs 4.0[0.0-13.5] P = 0.69; volume 124.8[10.9-338.8] vs 11.8 [0.0-190.2] P = 0.64 and SQUVmax 2.7[1.9-4.7]vs 1.7[0-3.5] P = 0.69). We found a strong positive correlation between BAT activity measured with (18)F-FDG and (123)I-mIBG in the whole group of BAT positive subjects (ρ=0.82, p<0.01).\\n\\nCONCLUSION: We conclude that both sympathetic drive and BAT activity are lower in older but not in obese males.","author":[{"dropping-particle":"","family":"Bahler","given":"Lonneke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verberne","given":"Hein J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Admiraal","given":"Wanda","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stok","given":"Wim J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soeters","given":"Maarten R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoekstra","given":"Joost B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holleman","given":"Frits","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Nuclear Medicine","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2016"]]},"page":"1-27","title":"Differences in Sympathetic Nervous Stimulation of Brown Adipose tissue between the young and old and the lean and obese.","type":"article-journal","volume":"57"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/oby.2011.125","ISBN":"1930-7381 (Print)\\r1930-7381 (Linking)","ISSN":"1930-7381","PMID":"21566561","abstract":"Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) combined with X-ray computed tomography (CT) in adult humans. The objective of this study was to clarify the relationship between BAT and adiposity in healthy adult humans, particularly to test the idea that decreased BAT activity may be associated with body fat accumulation with age. One hundred and sixty-two healthy volunteers aged 20-73 years (103 males and 59 females) underwent FDG-PET/CT after 2-h cold exposure at 19 °C with light clothing. Cold-activated BAT was detected in 41% of the subjects (BAT-positive). Compared with the BAT-negative group, the BAT-positive group was younger (P < 0.01) and showed a lower BMI (P < 0.01), body fat content (P < 0.01), and abdominal fat (P < 0.01). The incidence of cold-activated BAT decreased with age (P < 0.01), being more than 50% in the twenties, but less than 10% in the fifties and sixties. The adiposity-related parameters showed some sex differences, but increased with age in the BAT-negative group (P < 0.01), while they remained unchanged from the twenties to forties in the BAT-positive group, in both sexes. These results suggest that decreased BAT activity may be associated with accumulation of body fat with age.","author":[{"dropping-particle":"","family":"Yoneshiro","given":"Takeshi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aita","given":"Sayuri","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matsushita","given":"Mami","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Okamatsu-Ogura","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kameya","given":"Toshimitsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kawai","given":"Yuko","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyagawa","given":"Masao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tsujisaki","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saito","given":"Masayuki","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity (Silver Spring, Md.)","id":"ITEM-2","issue":"9","issued":{"date-parts":[["2011"]]},"page":"1755-60","publisher":"Nature Publishing Group","title":"Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans.","type":"article-journal","volume":"19"},"uris":[""]}],"mendeley":{"formattedCitation":"^32,33","plainTextFormattedCitation":"32,33","previouslyFormattedCitation":"^32,33"},"properties":{"noteIndex":0},"schema":""}32,33 and sexADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db10-0004","ISBN":"1939-327X (Electronic)\\n0012-1797 (Linking)","ISSN":"00121797","PMID":"20357363","abstract":"OBJECTIVE: Brown adipose tissue (BAT) regulates energy homeostasis and fat mass in mammals and newborns and, most likely, in adult humans. Because BAT activity and BAT mass decline with age in humans, the impact of BAT on adiposity may decrease with aging. In the present study we addressed this hypothesis and further investigated the effect of age on the sex differences in BAT activity and BAT mass.\\n\\nRESEARCH DESIGN AND METHODS: Data from 260 subjects (98 with BAT and 162 study date-matched control subjects) who underwent (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) under thermoneutral conditions were analyzed. BAT activity and BAT mass were determined in the upper body.\\n\\nRESULTS: BAT activity and BAT mass were higher in female (1.59 +/- 0.10 and 32 +/- 5 g vs. 1.02 +/- 0.10 and 18 +/- 4 g, both P < or = 0.0006) than in male subjects. In multivariate analyses, sex (P < 0.0001), age (P < 0.0001), and BMI (P = 0.0018) were associated independently with BAT activity. Interestingly, only in male subjects was there an interaction between BMI and age in determining BAT activity (P = 0.008) and BAT mass (P = 0.0002); BMI decreased with increasing BAT activity and BAT mass in the lowest age tertile (Spearman rank correlation coefficient r(s) = -0.38, P = 0.015 and r(s) = -0.37, P = 0.017, respectively), not in the higher age tertiles. Furthermore, BAT activity and mass differed between female and male subjects only in the upper two age tertiles (all P < or = 0.09).\\n\\nCONCLUSIONS: Our data corroborate that, in general, BAT activity and BAT mass are elevated in female subjects and in younger people. Importantly, we provide novel evidence that the impact of BAT activity and BAT mass on adiposity appears to decline with aging only in male subjects. Furthermore, while BAT activity and BAT mass only moderately decline with increasing age in female subjects, a much stronger effect is found in male subjects.","author":[{"dropping-particle":"","family":"Pfannenberg","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Werner","given":"Matthias K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ripkens","given":"Sabine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stef","given":"Irina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Deckert","given":"Annette","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmadl","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reimold","given":"Matthias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"H?ring","given":"Hans Ulrich","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Claussen","given":"Claus D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stefan","given":"Norbert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2010"]]},"page":"1789-1793","title":"Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans","type":"article-journal","volume":"59"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1210/jc.2010-0989","ISBN":"1945-7197 (Electronic)\\r0021-972X (Linking)","ISSN":"0021972X","PMID":"20943785","abstract":"CONTEXT In humans, the prevalence, mass, and glucose-uptake activity of (18)F-fluorodeoxyglucose ((18)F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. OBJECTIVE The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT in humans. RESEARCH DESIGN AND METHODS We retrospectively analyzed all (18)F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for (18)F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT depots was investigated. RESULTS Three hundred twenty-eight of the 4842 patients (6.8%) had (18)F-FDG-detected BAT. The prevalence of (18)F-FDG BAT was negatively associated with outdoor temperature (P < 0.0001), age (P < 0.0001), BMI (P < 0.0001), and diabetes status (P = 0.0003). Moreover, there was a significant age × sex interaction for the prevalence of (18)F-FDG BAT (the younger the subjects, the greater the sex difference). The mass and glucose-uptake activity of (18)F-FDG-detected BAT also decreased with increasing outdoor temperature (P < 0.0001), age (P < 0.0001), and BMI (P < 0.0001). They were lower in men than in women (P < 0.001) and lower in diabetic than in nondiabetic patients (P = 0.0002). CONCLUSIONS The present study identifies outdoor temperature, age, sex, BMI, and diabetes status as determinants of the prevalence, mass, and glucose-uptake activity of (18)F-FDG-detected BAT.","author":[{"dropping-particle":"","family":"Ouellet","given":"Veronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Routhier-Labadie","given":"Annick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bellemare","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lakhal-Chaieb","given":"Lajmi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Endocrinology and Metabolism","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2011"]]},"page":"192-199","title":"Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans","type":"article-journal","volume":"96"},"uris":[""]}],"mendeley":{"formattedCitation":"^31,132","plainTextFormattedCitation":"31,132","previouslyFormattedCitation":"^31,132"},"properties":{"noteIndex":0},"schema":""}31,132 were taken into consideration by recruiting only males under the age of 30, statistical analyses were limited as there was insufficient power to perform a multiple regression analysis (i.e. determine independent predictors of one’s change in FF at time points of interest)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.20982/tqmp.03.2.p043","ISBN":"1913-4126","ISSN":"1913-4126","abstract":"This article addresses the definition of power and its relationship to Type I and Type II errors. We discuss the relationship of sample size and power. Finally, we offer statistical rules of thumb guiding the selection of sample sizes large enough for sufficient power to detecting differences, associations, chi‐square, and factor analyses.","author":[{"dropping-particle":"","family":"Wilson VanVoorhis","given":"Carmen R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morgan","given":"Betsy L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Tutorials in Quantitative Methods for Psychology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2007"]]},"note":"From Duplicate 1 (Understanding Power and Rules of Thumb for Determining Sample Sizes - Wilson Betsy L, Carmen R.; Morgan)\n\nNULL","page":"43-50","title":"Understanding Power and Rules of Thumb for Determining Sample Sizes","type":"article-journal","volume":"3"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸⁶","plainTextFormattedCitation":"86","previouslyFormattedCitation":"⁸⁶"},"properties":{"noteIndex":0},"schema":""}86. Furthermore, despite the strengths of MRI, it does have inherent shortcomings. Participants have to remain perfectly still while images are being obtained, which made tolerating the cold exposure increasingly difficult. Furthermore, the resolution of the IDEAL sequence used to generate FF values is insufficient for differentiating between multiple cell types within a single voxelADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.21301","author":[{"dropping-particle":"","family":"Liu","given":"Chia-ying","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mckenzie","given":"Charles A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Huanzhou","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brittain","given":"Jean H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeder","given":"Scott B","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2007"]]},"page":"354-364","title":"Fat Quantification With IDEAL Gradient Echo Imaging : Correction of Bias From T 1 and Noise","type":"article-journal","volume":"364"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/jmri.22162.","ISBN":"8585348585","ISSN":"15378276","PMID":"1000000221","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"DL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"KS","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Goran","given":"MI","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagy","given":"TR","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-2","issue":"5","issued":{"date-parts":[["2010"]]},"page":"1195-1202","title":"Identification of Brown Adipose Tissue in Mice with Fat-Water IDEAL-MRI","type":"article-journal","volume":"31"},"uris":[""]}],"mendeley":{"formattedCitation":"^53,133","plainTextFormattedCitation":"53,133","previouslyFormattedCitation":"^53,133"},"properties":{"noteIndex":0},"schema":""}53,133. Since the human SCV region is heterogeneous in nature, especially among those who are overweight or obese (i.e. abundance of WAT interspersed within BAT)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61, it is particularly susceptible to these “partial volume effects”. Although the chosen FF and T2* thresholds were chosen in an attempt to separate “BAT-like” tissue from “non-BAT-like” tissue, partial-volume effects are often beyond the sensitivity of water-fat MRIADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61. Subsequent studies should consider reducing the voxel size (i.e. increase resolution)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1152/ajpendo.00482.2015","ISBN":"01931849","ISSN":"1522-1555","PMID":"27166284","abstract":"Activated brown adipose tissue (BAT) plays an important role in thermogenesis and whole body metabolism in mammals. Positron emission tomography (PET)-computed tomography (CT) imaging has identified depots of BAT in adult humans, igniting scientific interest. The purpose of this study is to characterize both active and inactive supraclavicular BAT in adults and compare the values to those of subcutaneous white adipose tissue (WAT). We obtained [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET-CT and magnetic resonance imaging (MRI) scans of 25 healthy adults. Unlike [(18)F]FDG PET, which can detect only active BAT, MRI is capable of detecting both active and inactive BAT. The MRI-derived fat signal fraction (FSF) of active BAT was significantly lower than that of inactive BAT (means ± SD; 60.2 ± 7.6 vs. 62.4 ± 6.8%, respectively). This change in tissue morphology was also reflected as a significant increase in Hounsfield units (HU; -69.4 ± 11.5 vs. -74.5 ± 9.7 HU, respectively). Additionally, the CT HU, MRI FSF, and MRI R2* values are significantly different between BAT and WAT, regardless of the activation status of BAT. To the best of our knowledge, this is the first study to quantify PET-CT and MRI FSF measurements and utilize a semiautomated algorithm to identify inactive and active BAT in the same adult subjects. Our findings support the use of these metrics to characterize and distinguish between BAT and WAT and lay the foundation for future MRI analysis with the hope that some day MRI-based delineation of BAT can stand on its own.","author":[{"dropping-particle":"","family":"Gifford","given":"Aliya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towse","given":"Theodore F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"Ronald C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Avison","given":"Malcolm J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Welch","given":"E. Brian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Physiology - Endocrinology And Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"page":"95-104","title":"Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging.","type":"article-journal","volume":"311"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶³","plainTextFormattedCitation":"63","previouslyFormattedCitation":"⁶³"},"properties":{"noteIndex":0},"schema":""}63 or experiment with intermolecular zero quantum coherence nuclear magnetic resonance spectroscopy alongside chemical-shift MRIADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.24369","ISBN":"1522-2594 (Electronic)\\r0740-3194 (Linking)","ISSN":"07403194","PMID":"22693111","abstract":"Approximately 130 attendees convened on February 19-22, 2012 for the first ISMRM-sponsored workshop on water-fat imaging. The motivation to host this meeting was driven by the increasing number of research publications on this topic over the past decade. The scientific program included an historical perspective and a discussion of the clinical relevance of water-fat MRI, a technical description of multiecho pulse sequences, a review of data acquisition and reconstruction algorithms, a summary of the confounding factors that influence quantitative fat measurements and the importance of MRI-based biomarkers, a description of applications in the heart, liver, pancreas, abdomen, spine, pelvis, and muscles, an overview of the implications of fat in diabetes and obesity, a discussion on MR spectroscopy, a review of childhood obesity, the efficacy of lifestyle interventional studies, and the role of brown adipose tissue, and an outlook on federal funding opportunities from the National Institutes of Health.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"B?rnert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hernando","given":"Diego","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kellman","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Jingfei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reeder","given":"Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sirlin","given":"Claude","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"378-388","title":"ISMRM workshop on fat-water separation: Insights, applications and progress in MRI","type":"article-journal","volume":"68"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁶","plainTextFormattedCitation":"66","previouslyFormattedCitation":"⁶⁶"},"properties":{"noteIndex":0},"schema":""}66 to determine if this reduces partial volume effects. Regardless of these technical limitations, numerous groups have commented on the difficulty of manually segmenting the SCV adipose tissue as its shape exhibits tremendous intersubject variabilityADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s10334-015-0498-z","ISBN":"1352-8661 (Electronic)\\r0968-5243 (Linking)","ISSN":"09685243","PMID":"26336839","abstract":"In this brief review, introductory concepts in animal and human adipose tissue segmentation using proton magnetic resonance imaging (MRI) and computed tomography are summarized in the context of obesity research. Adipose tissue segmentation and quantification using spin relaxation-based (e.g., T1-weighted, T2-weighted), relaxometry-based (e.g., T1-, T2-, T2*-mapping), chemical-shift selective, and chemical-shift encoded water-fat MRI pulse sequences are briefly discussed. The continuing interest to classify subcutaneous and visceral adipose tissue depots into smaller sub-depot compartments is mentioned. The use of a single slice, a stack of slices across a limited anatomical region, or a whole body protocol is considered. Common image post-processing steps and emerging atlas-based automated segmentation techniques are noted. Finally, the article identifies some directions of future research, including a discussion on the growing topic of brown adipose tissue and related segmentation considerations.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shen","given":"Wei","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Materials in Physics, Biology and Medicine","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2016"]]},"note":"From Duplicate 1 (Segmentation and quantification of adipose tissue by magnetic resonance imaging - Hu, Houchun Harry; Chen, Jun; Shen, Wei)\n\nNULL","page":"259-276","publisher":"Springer Berlin Heidelberg","title":"Segmentation and quantification of adipose tissue by magnetic resonance imaging","type":"article-journal","volume":"29"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0077907","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"24205024","abstract":"There is a major resurgence of interest in brown adipose tissue (BAT) biology, particularly regarding its determinants and consequences in newborns and infants. Reliable methods for non-invasive BAT measurement in human infants have yet to be demonstrated. The current study first validates methods for quantitative BAT imaging of rodents post mortem followed by BAT excision and re-imaging of excised tissues. Identical methods are then employed in a cohort of in vivo infants to establish the reliability of these measures and provide normative statistics for BAT depot volume and fat fraction. Using multi-echo water-fat MRI, fat- and water-based images of rodents and neonates were acquired and ratios of fat to the combined signal from fat and water (fat signal fraction) were calculated. Neonatal scans (n = 22) were acquired during natural sleep to quantify BAT and WAT deposits for depot volume and fat fraction. Acquisition repeatability was assessed based on multiple scans from the same neonate. Intra- and inter-rater measures of reliability in regional BAT depot volume and fat fraction quantification were determined based on multiple segmentations by two raters. Rodent BAT was characterized as having significantly higher water content than WAT in both in situ as well as ex vivo imaging assessments. Human neonate deposits indicative of bilateral BAT in spinal, supraclavicular and axillary regions were observed. Pairwise, WAT fat fraction was significantly greater than BAT fat fraction throughout the sample (ΔWAT-BAT = 38 %, p<10(-4)). Repeated scans demonstrated a high voxelwise correlation for fat fraction (Rall = 0.99). BAT depot volume and fat fraction measurements showed high intra-rater (ICCBAT,VOL = 0.93, ICCBAT,FF = 0.93) and inter-rater reliability (ICCBAT,VOL = 0.86, ICCBAT,FF = 0.93). This study demonstrates the reliability of using multi-echo water-fat MRI in human neonates for quantification throughout the torso of BAT depot volume and fat fraction measurements.","author":[{"dropping-particle":"","family":"Rasmussen","given":"Jerod M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Entringer","given":"Sonja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nguyen","given":"Annie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erp","given":"Theo G M","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guijarro","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oveisi","given":"Fariba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swanson","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piomelli","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wadhwa","given":"Pathik D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buss","given":"Claudia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potkin","given":"Steven G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"title":"Brown adipose tissue quantification in human neonates using water-fat separated MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"^69,134","plainTextFormattedCitation":"69,134","previouslyFormattedCitation":"^69,134"},"properties":{"noteIndex":0},"schema":""}69,134 and therefore makes standardization so challenging. Recent attempts at validating an automated segmentation tool for BAT in miceADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1007/s10334-015-0517-0","ISBN":"1033401505170","ISSN":"0968-5243","PMID":"26755063","abstract":"OBJECTIVE Brown adipose tissue (BAT) plays a key role for thermogenesis in mammals and infants. Recent confirmation of BAT presence in adult humans has aroused great interest for its potential to initiate weight-loss and normalize metabolic disorders in diabetes and obesity. Reliable detection and differentiation of BAT from the surrounding white adipose tissue (WAT) and muscle is critical for assessment/quantification of BAT volume. This study evaluates magnetic resonance (MR) acquisition for BAT and the efficacy of different automated methods for MR features-based BAT segmentation to identify the best suitable method. MATERIALS AND METHODS Multi-point Dixon and multi-echo T2 spin-echo images were acquired from 12 mice using an Agilent 9.4T scanner. Four segmentation methods: multidimensional thresholding (MTh); region-growing (RG); fuzzy c-means (FCM) and neural-network (NNet) were evaluated for the interscapular region and validated against manually defined BAT, WAT and muscle. RESULTS Statistical analysis of BAT segmentation yielded a median Dice-Statistical-Index, and sensitivity of 89. 92 % for NNet, 82. 86 % for FCM, 72. 74 % for RG, and 72. 70 %, for MTh, respectively. CONCLUSION This study demonstrates that NNet improves the specificity to BAT from surrounding tissue based on 3-point Dixon and T2 MRI. This method facilitates quantification and longitudinal measurement of BAT in preclinical-models and human subjects.","author":[{"dropping-particle":"","family":"Prakash","given":"K. N. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Srour","given":"Hussein","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velan","given":"Sendhil S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chuang","given":"Kai-Hsiang","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance Materials in Physics, Biology and Medicine","id":"ITEM-1","issue":"JANUARY","issued":{"date-parts":[["2016"]]},"page":"287-299","publisher":"Springer Berlin Heidelberg","title":"A method for the automatic segmentation of brown adipose tissue","type":"article-journal","volume":"29"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³⁵","plainTextFormattedCitation":"135","previouslyFormattedCitation":"¹³⁵"},"properties":{"noteIndex":0},"schema":""}135 and humansADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-01586-7","ISSN":"20452322","PMID":"28596551","abstract":"Human brown adipose tissue (BAT), with a major site in the cervical-supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervical-supraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R2(*) maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi-automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R2(*) and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice?=?0.93?±?0.03 (mean?±?standard deviation) and correlation coefficients of r?>?0.99 (P?<?0.0001) in FF, R2(*) and volume estimates, between the methods, were observed. Dice and BMI were positively correlated (r?=?0.54, P?=?0.03) but no other significant bias was obtained (P?≥?0.07). The automated method compared well with the reference method and can therefore be suitable for time-efficient and objective measurements in large cohort research studies of BAT.","author":[{"dropping-particle":"","family":"Lundstr?m","given":"Elin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Strand","given":"Robin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forslund","given":"Anders","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bergsten","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weghuber","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ahlstr?m","given":"H?kan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kullberg","given":"Joel","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2017"]]},"page":"1-12","title":"Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁴","plainTextFormattedCitation":"64","previouslyFormattedCitation":"⁶⁴"},"properties":{"noteIndex":0},"schema":""}64 have produced inconsistent findings, and therefore manual approaches are still the most reliable to date. Unlike the brain, where registration of a series of images is common practice to ensure consistent segmentation of a ROI, the appearance of the SCV region is extremely sensitive to even a slight change in position. In the present study, subjects would subconsciously shift between repeated scans, which removed the possibility of registration and necessitated manual segmentation of each individual image. Lastly, MRI does not offer a whole-body assessment of FF and is instead limited to a desired field of view. If this was not the case, the time course of other BAT (i.e. perirenal)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2015.09.007","ISBN":"1932-7420 (Electronic)\r1550-4131 (Linking)","ISSN":"19327420","PMID":"26445512","abstract":"Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.","author":[{"dropping-particle":"","family":"Kajimura","given":"Shingo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Spiegelman","given":"Bruce M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seale","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2015"]]},"page":"546-559","publisher":"Elsevier Inc.","title":"Brown and beige fat: Physiological roles beyond heat generation","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"¹²","plainTextFormattedCitation":"12","previouslyFormattedCitation":"¹²"},"properties":{"noteIndex":0},"schema":""}12 and SAT (i.e. abdominal) depots could have been simultaneously investigated.Before subjects began the cold exposure protocol, they were acclimatized to a ~21°C room wearing a tank top and shorts for 30 minutes. Though thermal comfort was obtained by offering blankets when a participant felt “cool”, true thermoneutrality before cold exposure was likely not achieved. The implications of not reaching thermoneutrality before cold exposure on subsequent BAT outcomes has been investigated by a number of independent groupsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jpeds.2012.04.056","ISBN":"1097-6833 (Electronic)\\n0022-3476 (Linking)","ISSN":"00223476","PMID":"22677567","abstract":"Objective: To establish the feasibility of infrared thermal imaging as a reproducible, noninvasive method for assessing changes in skin temperature within the supraclavicular region in vivo. Study design: Thermal imaging was used to assess the effect of a standard cool challenge (by placement of the participant's feet or hand in water at 20°C) on the temperature of the supraclavicular region in healthy volunteer participants of normal body mass index in 3 age groups, 3-8, 13-18, and 35-58 years of age. Results: We demonstrated a highly localized increase in temperature within the supraclavicular region together with a significant age-related decline under both baseline and stimulated conditions. Conclusion: Thermogenesis within the supraclavicular region can be readily quantified by thermal imaging. This noninvasive imaging technique now has the potential to be used to assess brown adipose tissue function alone, or in combination with other techniques, in order to determine the roles of thermogenesis in energy balance and, therefore, obesity prevention. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Symonds","given":"Michael E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Henderson","given":"Katrina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elvidge","given":"Lindsay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bosman","given":"Conrad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharkey","given":"Don","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Alan C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Budge","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of 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Thermogenesis","type":"article-journal","volume":"27"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin 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Brown","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"^{42,95,112,118}","plainTextFormattedCitation":"42,95,112,118","previouslyFormattedCitation":"^{42,95,112,118}"},"properties":{"noteIndex":0},"schema":""}42,95,112,118. In brief, Haq et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42 discovered that SCV skin temperature, as measured by IRT, gradually increased over the final 15 minutes of a 60-minute room temperature acclimation (20-23°C), suggesting that BAT was activated during this time. By using an acclimation temperature of 32°C to mask these effects, cold-induced increases in SCV skin temperature were concomitantly augmentedADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42. This is in accordance with Boon et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0098822","ISBN":"10.1371/journal.pone.0098822","ISSN":"19326203","PMID":"24922545","abstract":"BACKGROUND: Brown adipose tissue (BAT) has emerged as a novel player in energy homeostasis in humans and is considered a potential new target for combating obesity and related diseases. The current 'gold standard' for quantification of BAT volume and activity is cold-induced 18F-FDG uptake in BAT. However, use of this technique is limited by cost and radiation exposure. Given the fact that BAT is a thermogenic tissue, mainly located in the supraclavicular region, the aim of the current study was to investigate whether cold-induced supraclavicular skin temperature and core body temperature may be alternative markers of BAT activation in humans. SUBJECTS/METHODS: BAT volume and activity were measured in 24 healthy lean adolescent males (mean age 24.1±0.8 years), using cold-induced 18F-FDG uptake with PET-CT. Core body temperature was measured continuously in the small intestine with use of an ingestible telemetric capsule and skin temperature was measured by eighteen wireless iButtons attached to the skin following ISO-defined locations. RESULTS: Proximal and distal (hand/feet) skin temperatures markedly decreased upon cold exposure, while supraclavicular skin temperature significantly increased (35.2±0.1 vs. 35.5±0.1°C, p = 0.001). Furthermore, cold-induced supraclavicular skin temperature positively correlated with both total (R2 = 0.28, P = 0.010) and clavicular BAT volume (R2 = 0.20, P = 0.030) and clavicular SUVmax (R2 = 0.27, P = 0.010), while core body temperature did not. CONCLUSIONS: Supraclavicular skin temperature as measured by iButtons may have predictive value for BAT detection in adult humans. This is highly desirable considering the increasing interest in pharmacological interventions to stimulate BAT in human subjects. TRIAL REGISTRATION: NTR 2473.","author":[{"dropping-particle":"","family":"Boon","given":"Mari?tte R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bakker","given":"Leontine E H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Linden","given":"Rianne A D","non-dropping-particle":"Van Der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pereira Arias-Bouda","given":"Lenka","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smit","given":"Frits","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verberne","given":"Hein J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jazet","given":"Ingrid M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boon","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bakker","given":"Leontine E H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"Van Der","family":"Linden","given":"Rianne A D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arias-bouda","given":"Lenka Pereira","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smit","given":"Frits","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Verberne","given":"Hein J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lichtenbelt","given":"Wouter D Van Marken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jazet","given":"Ingrid M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rensen","given":"Patrick C N","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2014"]]},"note":"From Duplicate 2 (Supraclavicular skin temperature as a measure of18F-FDG uptake by BAT in human subjects - Boon, Mari?tte R.; Bakker, Leontine E H; Van Der Linden, Rianne A D; Pereira Arias-Bouda, Lenka; Smit, Frits; Verberne, Hein J.; Van Marken Lichtenbelt, Wouter D.; Jazet, Ingrid M.; Rensen, Patrick C N)\n\nNULL","page":"1-8","title":"Supraclavicular skin temperature as a measure of 18F-FDG uptake by BAT in human subjects","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"¹³⁶","plainTextFormattedCitation":"136","previouslyFormattedCitation":"¹³⁶"},"properties":{"noteIndex":0},"schema":""}136, who reported a similar finding after one-hour acclimation at 32°C. Using MRI, Stahl et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 measured the pre-cold changes in iBAT FF during 20 minutes of 23°C exposure and derived a rate of change of -1.3±0.9%/hour among 5 male subjects. Given this, cold-induced changes in the SCV BAT FF of subjects in the present study may have already begun during acclimation resulting in an underestimation of changes in FF. Subsequent investigations should consider sufficient warming (i.e. 32°C for 30-60 minutes) beforehand. With regards to more prolonged exposures, Sanchez-Guraches et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.10.008","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Sanchez-Gurmaches","given":"Joan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tang","given":"Yuefeng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jespersen","given":"Naja Zenius","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wallace","given":"Martina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Calejman","given":"Camila Martinez","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gujja","given":"Sharvari","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Huawei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Edwards","given":"Yvonne J.K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfrum","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Metallo","given":"Christian M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nielsen","given":"S?ren","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scheele","given":"Camilla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guertin","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018"]]},"page":"1-15","publisher":"Elsevier Inc.","title":"Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹²","plainTextFormattedCitation":"112","previouslyFormattedCitation":"¹¹²"},"properties":{"noteIndex":0},"schema":""}112 observed differential gene expression in the iBAT of WT mice housed at 30°C versus 22°C and 4°C, wherein those acclimatized to 22°C have an upregulation of thermogenic genes compared to those at 30°C, but not at 4°C. This notion alludes to the potential BAT-specific effects of a subject’s a priori acclimatization state (discussed in Section 5.2)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.004","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diwoky","given":"Clemens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schoiswohl","given":"Gabriele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Feiler","given":"Ursula","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wongsiriroj","given":"Nuttaporn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Abdellatif","given":"Mahmoud","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolb","given":"Dagmar","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoeks","given":"Joris","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sedej","given":"Simon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haemmerle","given":"Guenter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"753-763.e7","publisher":"Elsevier Inc.","title":"Cold-Induced Thermogenesis Depends on ATGL- Mediated Lipolysis in Cardiac Muscle, but Not Brown","type":"article-journal","volume":"26"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"^61,118","plainTextFormattedCitation":"61,118","previouslyFormattedCitation":"^61,118"},"properties":{"noteIndex":0},"schema":""}61,118, which might confound results and should therefore also be considered in future investigations.Given the apparent interplay between skeletal muscle and BAT-derived thermogenesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISSN":"1558-8238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"note":"NULL","title":"Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans","type":"article","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"doi:10.2967/jnumed.112.111336.","ISBN":"1535-5667 (Electronic)\\n0161-5505 (Linking)","ISSN":"1535-5667","PMID":"23362317","abstract":"UNLABELLED Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, PET imaging using the glucose analog (18)F-FDG has shown unequivocally the existence of functional BAT in adult humans, suggesting that many humans retain some functional BAT past infancy. The objective of this study was to determine to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and (18)F-FDG tracer uptake. METHODS Twenty-five healthy adults (15 women and 10 men; mean age ± SD, 30 ± 7 y) underwent triple-oxygen scans (H2(15)O, C(15)O, and (15)O2) as well as measurements of daily energy expenditure (DEE; kcal/d) both at rest and after exposure to mild cold (15.5°C [60°F]) using indirect calorimetry. The subjects were divided into 2 groups (high BAT and low BAT) based on the presence or absence of (18)F-FDG tracer uptake (standardized uptake value [SUV] > 2) in cervical-supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) were calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue. Regional blood oxygen saturation was determined by near-infrared spectroscopy. The total energy expenditure during rest and mild cold stress was measured by indirect calorimetry. Tissue-level metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to DEE. RESULTS The mass of activated BAT was 59.1 ± 17.5 g (range, 32-85 g) in the high-BAT group (8 women and 1 man; mean age, 29.6 ± 5.5 y) and 2.2 ± 3.6 g (range, 0-9.3 g) in the low-BAT group (9 men and 7 women; mean age, 31.4 ± 10 y). Corresponding maximal SUVs were significantly higher in the high-BAT group than in the low-BAT group (10.7 ± 3.9 vs. 2.1 ± 0.7, P = 0.01). Blood flow values were significantly higher in the high-BAT group than in the low-BAT group for BAT (12.9 ± 4.1 vs. 5.9 ± 2.2 mL/100 g/min, P = 0.03) and white adipose tissue (7.2 ± 3.4 vs. 5.7 ± 2.3 mL/100 g/min, P = 0.03) but were similar for muscle (4.4 ± 1.9 vs. 3.9 ± 1.7 mL/100 g/min). Moreover, OEF in BAT was similar in the 2 groups (0.51 ± 0.17 in high-BAT group vs. 0.47 ± 0.18 in low-BAT group, P = 0.39). During mild cold stress, calculated MRO2 values in BAT increased from 0.97 ± 0.53 to 1.42 ± 0.68 mL/100 g/min (P = 0.04) in the high-BAT group and were significantly higher than those determined in the low-BAT group (0.40…","author":[{"dropping-particle":"","family":"Muzik","given":"Otto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangner","given":"Thomas J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"William R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Ajay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Janisse","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013","4"]]},"note":"From Duplicate 2 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, Otto; Mangner, Thomas J; Leonard, William R; Kumar, Ajay; Janisse, James; Granneman, James G)\n\nFrom Duplicate 1 (15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat - Muzik, O; Manger, T; Leonard, WR; Kumar, A; Janisse, J; Granneman, JG)\n\nNULL","page":"523-531","publisher":"Society of Nuclear Medicine","title":"15O PET Measurement of Blood Flow and Oxygen Consumption in Cold-Activated Human Brown Fat","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹¹","plainTextFormattedCitation":"91","previouslyFormattedCitation":"⁹¹"},"properties":{"noteIndex":0},"schema":""}91,108,ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1074/jbc.M117.790451","author":[{"dropping-particle":"","family":"Bal","given":"Naresh C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Singh","given":"Sushant","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Reis","given":"Felipe C G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maurya","given":"Santosh K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pani","given":"Sunil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rowland","given":"LA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Periasamy","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Biological Chemistry","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-19","title":"Both brown adipose tissue and skeletal muscle thermogenesis processes are activated during mild to severe cold adaptation in mice","type":"article-journal","volume":"1"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1042/BSR20171087","author":[{"dropping-particle":"","family":"Bal","given":"Naresh C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maurya","given":"Santosh K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pani","given":"Sunil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sethy","given":"Chinmayee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Banerjee","given":"Ananya","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Das","given":"Sarita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Patanaik","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kundu","given":"CN","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Bioscience Reports","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"page":"1-17","title":"Mild cold induced thermogenesis : Are BAT and skeletal muscle synergistic partners?","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"^137,138","plainTextFormattedCitation":"137,138","previouslyFormattedCitation":"^137,138"},"properties":{"noteIndex":0},"schema":""}137,138ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Golozoubova","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hohtola","given":"Esa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Matthias","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jacobsson","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cannon","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The FASEB Journal","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2001"]]},"page":"2048-2050","title":"Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold","type":"article-journal","volume":"15"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1172/JCI60941","ISBN":"1558-8238 (Electronic)\\n0021-9738 (Linking)","ISSN":"00219738","PMID":"22269320","abstract":"That adult humans possess brown fat is now accepted - but is the brown fat metabolically active? Does human brown fat actually combust fat to release heat? In this issue of the JCI, Ouellet et al. demonstrate that metabolism in brown fat really is increased when adult humans are exposed to cold. This boosts the possibility that calorie combustion in brown fat may be of significance for our metabolism and, correspondingly, that the absence of brown fat may increase our proneness to obesity - provided that brown fat becomes activated not only by cold but also through food-related stimuli.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Investigation","id":"ITEM-2","issue":"2","issued":{"date-parts":[["2012"]]},"page":"486-489","title":"Yes, even human brown fat is on fire!","type":"article-journal","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"^113,139","plainTextFormattedCitation":"113,139","previouslyFormattedCitation":"^113,139"},"properties":{"noteIndex":0},"schema":""}113,139, an objective quantification of shivering using EMG would have added to the present findings. In other words, using EMG in parallel with BAT measurements would provide a quantification of thermogenic mechanisms occurring alongside NST during cold exposure. However, a commercially available MRI-safe EMG system was not available at the time of this study. Furthermore, the apparent dichotomy between shivering and non-shivering thermogenesis might not be as simplistic as current evidence presents it to be. Unlike Ouellett et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISSN":"1558-8238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"note":"NULL","title":"Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans","type":"article","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18, Blondin et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11 reported a non-significant relationship between shivering intensity and PET/CT-markers of BAT activity. Instead, this group suggested that deep muscles proximal to the spinal cord, which are not easily recorded by EMG, are preferentially recruited by thermogenesisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹","plainTextFormattedCitation":"11","previouslyFormattedCitation":"¹¹"},"properties":{"noteIndex":0},"schema":""}11. Furthermore, Vijgen et al.ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0017247","ISBN":"1932-6203","ISSN":"19326203","PMID":"21390318","abstract":"BACKGROUND: Cold-stimulated adaptive thermogenesis in brown adipose tissue (BAT) to increase energy expenditure is suggested as a possible therapeutic target for the treatment of obesity. We have recently shown high prevalence of BAT in adult humans, which was inversely related to body mass index (BMI) and body fat percentage (BF%), suggesting that obesity is associated with lower BAT activity. Here, we examined BAT activity in morbidly obese subjects and its role in cold-induced thermogenesis (CIT) after applying a personalized cooling protocol. We hypothesize that morbidly obese subjects show reduced BAT activity upon cold exposure.\\n\\nMETHODS AND FINDINGS: After applying a personalized cooling protocol for maximal non-shivering conditions, BAT activity was determined using positron-emission tomography and computed tomography (PET-CT). Cold-induced BAT activity was detected in three out of 15 morbidly obese subjects. Combined with results from lean to morbidly obese subjects (n?=?39) from previous study, the collective data show a highly significant correlation between BAT activity and body composition (P<0.001), respectively explaining 64% and 60% of the variance in BMI (r?=?0.8; P<0.001) and BF% (r?=?0.75; P<0.001). Obese individuals demonstrate a blunted CIT combined with low BAT activity. Only in BAT-positive subjects (n?=?26) mean energy expenditure was increased significantly upon cold exposure (51.5±6.7 J/s versus 44.0±5.1 J/s, P?=?0.001), and the increase was significantly higher compared to BAT-negative subjects (+15.5±8.9% versus +3.6±8.9%, P?=?0.001), indicating a role for BAT in CIT in humans.\\n\\nCONCLUSIONS: This study shows that in an extremely large range of body compositions, BAT activity is highly correlated with BMI and BF%. BAT-positive subjects showed higher CIT, indicating that BAT is also in humans involved in adaptive thermogenesis. Increasing BAT activity could be a therapeutic target in (morbid) obesity.","author":[{"dropping-particle":"","family":"Vijgen","given":"Guy H E J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bouvy","given":"Nicole D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Teule","given":"G. J Jaap","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2011"]]},"note":"NULL","page":"2-7","title":"Brown adipose tissue in morbidly obese subjects","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴⁰","plainTextFormattedCitation":"140","previouslyFormattedCitation":"¹⁴⁰"},"properties":{"noteIndex":0},"schema":""}140 found a high individual variation in the onset of shivering as detected by EMG, even among morphologically similar subjects. Lastly, the emerging idea that muscles themselves participate in NST adds another dimension to our already convoluted understanding of cold toleranceADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3389/fphys.2017.00889","author":[{"dropping-particle":"","family":"Nowack","given":"Julia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Giroud","given":"Sylvain","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnold","given":"Walter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ruf","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Frontiers in Physiology","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1-13","title":"Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴¹","plainTextFormattedCitation":"141","previouslyFormattedCitation":"¹⁴¹"},"properties":{"noteIndex":0},"schema":""}141. Beta-adrenergic agonists and sympathomimetics could overcome this limitation, but their use in humans presents added systemic complicationsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1207911109","ISBN":"0027-8424","ISSN":"1091-6490","PMID":"22665804","abstract":"As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by (18)F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.","author":[{"dropping-particle":"","family":"Cypess","given":"Aaron M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Yih-Chieh","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sze","given":"Cathy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Ke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"English","given":"Jeffrey","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chan","given":"Onyee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holman","given":"Ashley R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tal","given":"Ilan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Palmer","given":"Matthew R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kolodny","given":"Gerald M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C Ronald","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"25","issued":{"date-parts":[["2012","6"]]},"page":"10001-10005","publisher":"National Academy of Sciences","title":"Cold but not sympathomimetics activates human brown adipose tissue in vivo.","type":"article-journal","volume":"109"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1007/s00125-012-2748-1","author":[{"dropping-particle":"","family":"Carey","given":"A L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Formosa","given":"M F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Every","given":"B","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bertovic","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikelis","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lambert","given":"G.W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kalff","given":"V","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Duffy","given":"S.J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cherk","given":"M.H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kingwell","given":"B.A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetologia","id":"ITEM-2","issued":{"date-parts":[["2013"]]},"page":"147-155","title":"Ephedrine activates brown adipose tissue in lean but not obese humans","type":"article-journal","volume":"56"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.2337/db12-0288.","author":[{"dropping-particle":"","family":"Vosselman","given":"Maarten J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wierts","given":"Roel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baak","given":"Marleen A","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"Patrick","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-3","issue":"December","issued":{"date-parts":[["2012"]]},"page":"3106-3113","title":"Systemic beta-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"^34,142,143","plainTextFormattedCitation":"34,142,143","previouslyFormattedCitation":"^34,142,143"},"properties":{"noteIndex":0},"schema":""}34,142,143. Regardless, even participants matched based on age and body composition can differ in their response to coldADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2016.07.014","ISSN":"19327420","abstract":"Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked.","author":[{"dropping-particle":"","family":"Chen","given":"Kong Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Laughlin","given":"Maren R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haft","given":"Carol R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Houchun Harry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bredella","given":"Miriam A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Enerb?ck","given":"Sven","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kinahan","given":"Paul E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lichtenbelt","given":"Wouter Van Marken","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Frank I.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sunderland","given":"John J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Virtanen","given":"Kirsi A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wahl","given":"Richard L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2016"]]},"page":"210-222","title":"Perspective Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans","type":"article-journal","volume":"24"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁸","plainTextFormattedCitation":"48","previouslyFormattedCitation":"⁴⁸"},"properties":{"noteIndex":0},"schema":""}48, and it is therefore important that, in addition to shivering, cold-induced measures of whole-body heat production (e.g. indirect calorimetry and/or monitoring of the inlet and outlet temperature of a liquid-perfused garment, the latter of which was performed for 6 participants), and changes in mean skin temperature (MST) be made concurrent with BAT measurements ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2217/clp.15.14","ISSN":"17584302 17584299","abstract":"The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques.","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P DP","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Lipidology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"259-280","title":"A critical appraisal of brown adipose tissue metabolism in humans","type":"article-journal","volume":"10"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴⁷","plainTextFormattedCitation":"47","previouslyFormattedCitation":"⁴⁷"},"properties":{"noteIndex":0},"schema":""}47. With this holistic assessment of cold-induced thermoregulation, BAT’s relevance in the realm of whole-body systemic thermogenesis can be evaluated based on the following relationship: Hprod (via indirect calorimetry or inlet-outlet) = ST (via EMG) + NST (via BAT). Therefore, should MR-safe approaches to whole-body heat production and MST be available, they should certainly be taken into consideration by researchers hoping to standardize this investigation before employing larger and more heterogeneous cohorts.Finally, considering one’s state of physical endurance in addition to their thermal history might have helped to explain the observed intersubject variation in BAT FF changesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1017/S0029665112000584","ISBN":"1475-2719 (Electronic)\\n0029-6651 (Linking)","ISSN":"1475-2719","PMID":"22704581","abstract":"Since the rediscovery of brown adipose tissue (BAT) in adult human subjects in 2007, there has been a dramatic resurgence in research interest in its role in heat production and energy balance. This has coincided with a reassessment of the origins of BAT and the suggestion that brown preadipocytes could share a common lineage with skeletal myoblasts. In precocial newborns, such as sheep, the onset of non-shivering thermogenesis through activation of the BAT-specific uncoupling protein 1 (UCP1) is essential for effective adaptation to the cold exposure of the extra-uterine environment. This is mediated by a combination of endocrine adaptations which accompany normal parturition at birth and further endocrine stimulation from the mother's milk. Three distinct adipose depots have been identified in all species studied to date. These contain either primarily white, primarily brown or a mix of brown and white adipocytes. The latter tissue type is present, at least, in the fetus and, thereafter, appears to take on the characteristics of white adipose tissue during postnatal development. It is becoming apparent that a range of organ-specific mechanisms can promote UCP1 expression. They include the liver, heart and skeletal muscle, and involve unique endocrine systems that are stimulated by cold exposure and/or exercise. These multiple pathways that promote BAT function vary with age and between species that may determine the potential to be manipulated in early life. Such interventions could modify, or reverse, the normal ontogenic pathway by which BAT disappears after birth, thereby facilitating BAT thermogenesis through the life cycle.","author":[{"dropping-particle":"","family":"Symonds","given":"Michael E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pope","given":"Mark","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Budge","given":"Helen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Proceedings of the Nutrition Society","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2012"]]},"note":"NULL","page":"363-70","title":"Adipose tissue development during early life: novel insights into energy balance from small and large mammals.","type":"article-journal","volume":"71"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1152/physrev.00015.2003","ISBN":"0031-9333 (Print) 0031-9333 (Linking)","ISSN":"0031-9333","PMID":"14715917","abstract":"The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogen-esis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.","author":[{"dropping-particle":"","family":"Cannon","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiological Reviews","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2004"]]},"page":"277-359","title":"Brown Adipose Tissue: Function and Physiological Significance","type":"article-journal","volume":"84"},"uris":[""]}],"mendeley":{"formattedCitation":"^6,144","plainTextFormattedCitation":"6,144","previouslyFormattedCitation":"^6,144"},"properties":{"noteIndex":0},"schema":""}6,144. This study also did not control for the type of movie or TV show that subjects watched over the course of cooling, which might have created unwanted variability in the amount of sympathetic stimuli one received. Lastly, combined PET-MRI would permit quantification of FF and PET-specific radiotracers (i.e. BAT oxidative metabolism using 11C-acetateADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISBN":"1558-8238 (Electronic)\\r0021-9738 (Linking)","ISSN":"00219738 15588238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of clinical investigation","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"page":"545","title":"Brown adipose tissue oxidative metabolism contributles to energy expenditure during cold exposure in humans","type":"article-journal","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁸","plainTextFormattedCitation":"78","previouslyFormattedCitation":"⁷⁸"},"properties":{"noteIndex":0},"schema":""}78, perfusion using 15O-H2OADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2967/jnumed.116.180992","ISSN":"0161-5505","PMID":"27789721","abstract":"OBJECTIVE Recent work in rodents has demonstrated that basal activity of local sympathetic nervous system is critical for maintaining brown adipocyte phenotypes in classic brown (BAT) and white adipose tissue (WAT). Accordingly, we sought to assess the relationship between sympathetic innervation and cold-induced activation of BAT and WAT, and its relation to local and whole body daily energy expenditure (DEE, kcal/d) in lean young adults. METHODS Twenty adult lean normal subjects (10F/10M, 23.3 + 3.8 years, BMI = 23.7 + 2.5) underwent (11)C-meta-hydroxyephedrin (HED) and (15)O-water PET imaging at rest and following exposure to mild cold (16oC) temperature. In addition, (18)F-fluorodeoxyglucose (FDG) images were obtained during the cold stress condition to assess cold-activated BAT mass. Subjects were divided into two groups (High-BAT, Low-BAT) based on the presence of FDG tracer uptake (SUV > 2) in supraclavicular BAT (-150 < HU < -50). Blood flow and HED retention index (RI, an indirect measure of sympathetic innervation) were calculated from dynamic PET scans at the location of BAT, WAT, muscle and visceral WAT. Whole body DEE during rest and cold stress was measured by indirect calorimetry. Tissue level oxygen consumption (MRO2) in BAT was determined and used to calculate the contribution of cold-activated BAT and WAT to daily DEE. RESULTS FDG uptake identified subjects with high and low levels of cold-activated BAT mass (High-BAT, 96 + 37g; Low-BAT 16 + 4g). HED RI under thermoneutral conditions significantly predicted FDG uptake during cold stress (R2 = 0.68, p<0.01). The HED RI during cold stress was also highly correlated with FDG uptake (R2 = 0.73, p<0.01). In contrast to the significant increase of HED RI during cold in BAT (3.43+0.93 vs. 2.42+0.85, P = 0.02), cold exposure decreased the HED RI in WAT (0.44+0.22 vs. 0.41+0.18) as a consequence of decreased perfusion (1.22+0.20 vs. 1.12+0.16 ml/100g/min). Overall, blood flow, HED RI and SUV in BAT and WAT were highly correlated (R2~0.8), demonstrating a tight coupling between perfusion, sympathetic innervation and glucose uptake. The contribution of WAT to whole body DEE was ~150 kcal/day at rest (149+52 kcal/day) which decreased to ~100 kcal/day during cold (102+47 kcal/day). CONCLUSION The level of sympathetic innervation, as determined by HED RI, can predict levels of functional BAT, as determined by FDG uptake. Overall, blood flow is the best independent predictor of HED RI and FDG uptake …","author":[{"dropping-particle":"","family":"Muzik","given":"Otto","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mangner","given":"Tom J Thomas J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leonard","given":"William R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kumar","given":"Ajay","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Nuclear Medicine","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"799-807","title":"Sympathetic Innervation of Cold-Activated Brown and White Fat in Lean Young Adults","type":"article-journal","volume":"59"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴⁵","plainTextFormattedCitation":"145","previouslyFormattedCitation":"¹⁴⁵"},"properties":{"noteIndex":0},"schema":""}145, or FFA uptake using 18F-FTHAADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁰","plainTextFormattedCitation":"20","previouslyFormattedCitation":"²⁰"},"properties":{"noteIndex":0},"schema":""}20) during the same cold exposure session. However, since ionizing radiation is a notable limitation of PET, and that these tracers are largely inaccessible in most research centers, the general feasibility of this approach in a time course context is limited. Applicability of similar approaches using MRI and hyperpolarized substrates, such as 129Xe (i.e. tissue perfusion) and 13C (i.e. oxidation), are currently being explored as a means to overcome this barrierADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1073/pnas.1403697111","author":[{"dropping-particle":"","family":"Tamara","given":"Rosa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"He","given":"Ting","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floyd","given":"CS Carlos S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freeman","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"White","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"RT","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"He","given":"Ting","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floyd","given":"CS Carlos S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freeman","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"White","given":"Christian","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Proceedings of the National Academy of Sciences","id":"ITEM-1","issue":"50","issued":{"date-parts":[["2014"]]},"page":"18001-18006","title":"Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI","type":"article-journal","volume":"111"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/ijo.2013.58","ISBN":"1476-5497 (Electronic)\\r0307-0565 (Linking)","ISSN":"0307-0565","PMID":"23689358","abstract":"Objective:The recent identification of functional depots of brown adipose tissue (BAT) in adult humans has potential implications for the treatment of obesity. In order to evaluate new therapies aimed at inducing the production of more BAT or activating BAT in humans, it will be important to develop noninvasive methods to assess the functional state of the tissue in vivo. In this study, we investigate the feasibility of using hyperpolarized (13)C imaging to noninvasively identify functional, activated BAT in an in vivo rodent model, in less than 1 min, following an infusion of pre-polarized [1-(13)C] pyruvate.Design:Hyperpolarized (13)C imaging was used to monitor BAT metabolic conversion of pre-polarized [1-(13)C] pyruvate in rats during baseline and norepinephrine (NE)-stimulated conditions.Results:Activated BAT, stimulated by NE injection, can be detected in rats by increased conversion of pre-polarized [1-(13)C] pyruvate into its downstream products (13)C bicarbonate and [1-(13)C] lactate. The colocalization of the (13)C signal to interscapular BAT was validated using hematoxylin-eosin histological staining.Conclusion:The radiation-free nature and recent translation into the clinic of the hyperpolarized (13)C-imaging test may potentially facilitate trials of therapeutics targeting BAT activation in humans.","author":[{"dropping-particle":"","family":"Lau","given":"AZ Z","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"AP P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gu","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladouceur-Wodzak","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nayak","given":"KS S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cunningham","given":"CH H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2014"]]},"page":"126-131","title":"Noninvasive identification and assessment of functional brown adipose tissue in rodents using hyperpolarized 13C imaging","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"^146,147","plainTextFormattedCitation":"146,147","previouslyFormattedCitation":"^146,147"},"properties":{"noteIndex":0},"schema":""}146,147.Next StepsFirst, this study design should be extended to larger and more heterogeneous cohorts to develop a time course that is representative of a diverse population of individuals. In accomplishing this, the predictive value of a mathematical model describing the change in FF over time would inherently be improved. However, in order for a study of this nature to be feasible, a reliable and reproducible automatic segmentation algorithm for SCV BAT must be developed. Second, the effects of a warmer acclimation period (i.e. 30 minutes at 32°C)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42 should be compared against what was performed in the current study to determine if the magnitude of change in FF was indeed masked. Third, all variables in the thermogenesis equation (i.e. Hprod = ST + NST) should be accounted when making BAT-specific conclusions. Fourth, the potentially unique thermogenic properties of the posterior neck SAT should be explored by future trials (i.e. using the same FF and T2* thresholds as the SCV region). Finally, studies that wish to measure MRI-derived changes in BAT with a shorter duration of cold exposure should further investigate the utility of AUC by reproducing previous associations with established covariates of BAT activity. APPENDIX38519101571625Figure SEQ Figure \* ARABIC 10 - Figure 6 from Hu et al. (2013) showing FF and T2* signatures from SCV BAT (gray) and subcutaneous WAT (black) for a lean 18 year old-female participant.0Figure SEQ Figure \* ARABIC 10 - Figure 6 from Hu et al. (2013) showing FF and T2* signatures from SCV BAT (gray) and subcutaneous WAT (black) for a lean 18 year old-female participant.8312747942500Supplementary Material (Introduction)Table SEQ Table \* ARABIC 7 - Time Course Measurements (Humans)ReferencePopulationBAT StimulationModality for BAT DetectionFindingsOuelette et al. (2012)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1172/JCI60433DS1","ISSN":"1558-8238","PMID":"22269323","author":[{"dropping-particle":"","family":"Ouellet","given":"Véronique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2012"]]},"note":"NULL","title":"Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans","type":"article","volume":"122"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁸","plainTextFormattedCitation":"18","previouslyFormattedCitation":"¹⁸"},"properties":{"noteIndex":0},"schema":""}18- Healthy males (n=6, 23-42 years, “normal” BMI)- Acute cold exposure (180 minutes at 18°C)- 18F-FDG, 11C-acetate, and 18FTHA PET/CT- Dynamic PET acquisition- Figure 4B is the time-radioactivity curve of 11C-acetate in BAT, which shows immediate uptake and maximal radioactivity at 60 seconds, after which it normalizesVan Rooijen et al. (2013)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/RLI.0b013e31829363b8","ISSN":"1536-0210","PMID":"23695084","abstract":"OBJECTIVES: The objective of this study was to explore the use of magnetic resonance imaging (MRI) to identify and quantify active brown adipose tissue (BAT) in adult humans. 2-Deoxy-2-[F]fluoro-D-glucose (FDG) positron emission tomography (PET) combined with computed tomography was used as a reference method to identify active BAT depots and to guide the MRI data analysis. MATERIALS AND METHODS: The ethics committee of the institute approved the protocol, and all participants provided written informed consent before participation. Both PET combined with computed tomography and MRI of BAT were performed in 11 healthy volunteers. Brown adipose tissue was activated by cooling the participants using a dedicated water-perfused suit. For the MRI examination of BAT, water-fat imaging and dynamic T2* imaging were performed at an effective temporal resolution of 2 minutes per volume. Water-fat images were derived from a multiecho MRI sequence using the Dixon technique. RESULTS: 2-Deoxy-2-[F]fluoro-D-glucose-PET identified active BAT in 8 of the 11 participants. Water-fat MRI showed that BAT depots had a fat fraction of 65.2% (7.0%) compared with 81.5% (5.4%) for the subcutaneous white adipose tissue (paired difference of 16.3% [4.9%]; P < 0.05). Dynamic T2* imaging during cold stimulation revealed signal fluctuations that were sensitive to BAT activation. The presence of these components correlated with BAT activation quantified from FDG-PET (r = 0.63; P < 0.05). CONCLUSIONS: Although FDG-PET has superior contrast for identifying active BAT, the MRI temporal resolution provides insight in activation dynamics. In addition, the flexibility of MRI allows for simultaneous mapping of tissue fat content and functional responses. The results indicate that MRI is a promising addition to PET for the identification of BAT and its activity responses to stimulation. An MRI-based methodology to quantify BAT activity is a highly desirable step in addressing the role of BAT in obesity disorders.","author":[{"dropping-particle":"","family":"Rooijen","given":"Bart D","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lans","given":"Anouk A J J","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brans","given":"Boudewijn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wildberger","given":"Joachim E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mottaghy","given":"Felix M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schrauwen","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Backes","given":"WH.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter David","non-dropping-particle":"van","parse-names":false,"suffix":""}],"container-title":"Investigative radiology","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2013"]]},"page":"708-714","title":"Imaging cold-activated brown adipose tissue using dynamic T2*-weighted magnetic resonance imaging and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography.","type":"article-journal","volume":"48"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁷","plainTextFormattedCitation":"67","previouslyFormattedCitation":"⁶⁷"},"properties":{"noteIndex":0},"schema":""}67- Healthy adults (n=11, 7F, 4M, 21-28 years, “normal” BMI, “overweight” BMI)- Acute cooling paradigm (two bouts of 10 minutes at NST)- 2-Deoxy-2- 18F-FDG PET/CT- Dynamic T2* MRI- Temporal fluctuation in T2* signal that correlates with the cooling paradigm (figure 4D in paper)Hanssen et al. 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(2015)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"1doi:10.1038/ijo.2015.76","ISBN":"0324141122","ISSN":"1527-5418","author":[{"dropping-particle":"","family":"Annamalai","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chondronikola","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porter","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"MK","given":"Saraf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cesani","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sidossis","given":"LS","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Int J Obes","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1561-1564","title":"A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans","type":"article-journal","volume":"39"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴⁸","plainTextFormattedCitation":"148","previouslyFormattedCitation":"¹⁴⁸"},"properties":{"noteIndex":0},"schema":""}148- Healthy adults (n=23)*No other information available- Acute cold exposure (2-6 hours total, including NST)- 2-Deoxy-2-D- 18F-FDG PET/CT- Figure 2D shows the respiratory capacity of human SCV BAT tissue by addition of substrates, inhibitors, and uncouplers, which suggests maximal BAT activation within ~5 minutesStahl et al. (2016)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56- Healthy adults (n=10, 5F, 5M, 23-30 years, “normal” BMI)- Acute cold exposure (90 minutes at 12°C)- MRI- Figure 4 shows time to nadir FF in BAT: S01: 90 mins; S02: 85 mins; S03: 70 mins; S04: 60 mins; S06: 60 mins; S07: 60 mins; S08: 60 mins; S09: 55 mins; S10: 75 mins (average = ~60 minutes)- Only 2 subjects recovered FF during warming (S07 and S09), whereas S01 and S03 showed decreasesHaq et al. (2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41598-017-11537-x","ISSN":"2045-2322","author":[{"dropping-particle":"","family":"Haq","given":"Tahniyah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Crane","given":"Justin D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanji","given":"Sarah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gunn","given":"Elizabeth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tarnopolsky","given":"Mark A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gerstein","given":"Hertzel C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steinberg","given":"Gregory R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morrison","given":"Katherine M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"1-9","publisher":"Springer US","title":"Optimizing the methodology for measuring supraclavicular skin temperature using infrared thermography ; implications for measuring brown adipose tissue activity in humans","type":"article-journal","volume":"7"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴²","plainTextFormattedCitation":"42","previouslyFormattedCitation":"⁴²"},"properties":{"noteIndex":0},"schema":""}42- Healthy males (n=62, 18-39 years, all BMI categories)- Acute cold exposure (60 minutes at 12°C)- Infrared Thermography (IRT)- Figure 3 shows that cold elicits a rapid change in SCV skin temperature, however this increase plateaus at 15-20 minutes and declines steadily until the end of the 60 minute exposure (top and middle lines in Figure 3)McCallister et al. (2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁴","plainTextFormattedCitation":"74","previouslyFormattedCitation":"⁷⁴"},"properties":{"noteIndex":0},"schema":""}74- Healthy adults (n=16, 7F, 9M, 21-49 years, all BMI categories)- Acute cold exposure (2-2.5 hours at NST)- 18F-FDG PET/MRI- Figure 9 and Supplementary Figure 4 presents BAT FF time course descriptions as follows: Subject A (lean 24 year old M): Initial increase at around 20 minutes, then steady decrease until end (no time to nadir FF) Subject B (overweight 30 year old M: Slight decrease until 50 minutes (nadir FF), and then increase until end of exposure Subject C (lean 30 year old F): Slight decrease until around 80 mins (nadir FF), increased to above baseline FF at end Subject E (lean 25 year old M): Gradual decrease throughout (no time to nadir FF) Subject F (lean 20 year old M): Up and down pattern throughout (time to nadir FF around 50 mins) Subject G (lean 25 year old F): Up and down (no net FF change, time to nadir FF before 50 mins) Average time to nadir FF, if it did appear, occurred around 60 minsBlondin et al. (2015)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2337/db14-1651","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kunach","given":"Margaret","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Diabetes","id":"ITEM-1","issued":{"date-parts":[["2015"]]},"page":"2388-2397","title":"Selective Impairment of Glucose but Not Fatty Acid or Oxidative Metabolism in Brown Adipose Tissue of Subjects With Type 2 Diabetes","type":"article-journal","volume":"64"},"uris":[""]}],"mendeley":{"formattedCitation":"²⁰","plainTextFormattedCitation":"20","previouslyFormattedCitation":"²⁰"},"properties":{"noteIndex":0},"schema":""}20- Healthy young adults (n=6; 22-26 years; normal/overweight BMI), type 2 diabetics (n=6; 56-64 years; all BMI categories)), age-matched controls (n=7; 56-62 years; normal/overweight BMI)- Acute cold exposure (180 minutes at 18°C)11C-acetate PET/CT- Figure 3B shows a time reactivity curve of BAT 11C over for healthy young controls, who had an initial increase over the first ~80 seconds, after which it fell towards baselineReber et al. (2018)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2018.02.002","ISSN":"19327420","PMID":"29514074","abstract":"Metabolism is a fundamental process of life. However, non-invasive measurement of local tissue metabolism is limited today by a deficiency in adequate tools for in vivo observations. We designed a multi-modular platform that explored the relation between local tissue oxygen consumption, determined by label-free optoacoustic measurements of hemoglobin, and concurrent indirect calorimetry obtained during metabolic activation of brown adipose tissue (BAT). By studying mice and humans, we show how video-rate handheld multi-spectral optoacoustic tomography (MSOT) in the 700–970 nm spectral range enables non-invasive imaging of BAT activation, consistent with positron emission tomography findings. Moreover, we observe BAT composition differences between healthy and diabetic tissues. The study consolidates hemoglobin as a principal label-free biomarker for longitudinal non-invasive imaging of BAT morphology and bioenergetics in situ. We also resolve water and fat components in volunteers, and contrast MSOT readouts with magnetic resonance imaging data. Reber et al. employed label-free multi-spectral optoacoustic tomography to non-invasively image BAT and WAT in mice and humans and resolve BAT activation based on hemoglobin gradients. The 700–970 nm spectral range further enabled identification of BAT composition using lipid and water signatures.","author":[{"dropping-particle":"","family":"Reber","given":"Josefine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Willersh?user","given":"Monja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karlas","given":"Angelos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Paul-Yuan","given":"Korbinian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Diot","given":"Gael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franz","given":"Daniela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fromme","given":"Tobias","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Ovsepian","given":"Saak","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bézière","given":"Nicolas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dubikovskaya","given":"Elena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Karampinos","given":"Dimitrios C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holzapfel","given":"Christina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hauner","given":"Hans","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Klingenspor","given":"Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ntziachristos","given":"Vasilis","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2018"]]},"page":"689-701","title":"Non-invasive Measurement of Brown Fat Metabolism Based on Optoacoustic Imaging of Hemoglobin Gradients","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁷","plainTextFormattedCitation":"107","previouslyFormattedCitation":"¹⁰⁷"},"properties":{"noteIndex":0},"schema":""}107- Healthy humans (n=3)*No other details provided- Acute cold exposure (13°C)- Multi-spectral optoacoustic tomography (MSOT)- Figure 5I shows a time course of VO2 and HbO2 (oxygenated Hb, the MSOT signal), which peak within minutes of stimulationTable SEQ Table \* ARABIC 8 - Time Course Measurements (Animals)ReferencePopulationBAT StimulationModality for BAT DetectionFindingsXian Yu et al. (2002)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Yu","given":"Xing Xian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lewin","given":"David A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Forrest","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Adams","given":"Sean H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The FASEB Journal","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2002"]]},"page":"155-168","title":"Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo","type":"article-journal","volume":"16"},"uris":[""]}],"mendeley":{"formattedCitation":"²³","plainTextFormattedCitation":"23","previouslyFormattedCitation":"²³"},"properties":{"noteIndex":0},"schema":""}23- Healthy mice (n=?)- Cold (48 hours at 4°C)- RT-PCR for iBAT gene expression- Figure 6 presents the expression of various BAT-related genes, including the following: Cluster 1: GLUT1-3 inhibited by acute (1-24hours) but not chronic (24-48 hours) cold Cluster 2: UCP1 and LPL expression increased in response to cold (6-24 hours) Cluster 3: FAS increase during first hour, then drops until 6 hours Cluster 5: MG Lipase increases during first hour, then decrease until 6 hoursMotillo et al. (2012)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1074/jbc.M112.374041","ISBN":"4431987398","author":[{"dropping-particle":"","family":"Mottillo","given":"Emilio P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bloch","given":"Ainsley E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leff","given":"Todd","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Granneman","given":"James G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Neurosciences","given":"Behavioral","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Biological Chemistry","id":"ITEM-1","issue":"30","issued":{"date-parts":[["2012"]]},"page":"25038-25048","title":"Lipolytic Products Activate Peroxisome Proliferator-activated Receptor ( PPAR ) aplha and delta in Brown Adipocytes to Match Fatty Acid Oxidation with Supply","type":"article-journal","volume":"287"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁸","plainTextFormattedCitation":"98","previouslyFormattedCitation":"⁹⁸"},"properties":{"noteIndex":0},"schema":""}98- Healthy mice (n=11)- B3-adrenergic agonist (CL-316,243)- Live cell fluorescent reporter assay of PPAR activation- Ligands for PPAR alpha and delta (receptors that modulate induction of oxidative genes) are detected at the lipid droplet surface within minutes of PKA activation (i.e. lipolysis) and can transcriptionally activate PPAR alpha and gamma over a period of hours (i.e. expansion of oxidative capacity to match growing FFA supply)Chen et al. (2012)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/oby.2012.22.Anatomical","author":[{"dropping-particle":"","family":"Chen","given":"Y I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cypess","given":"Aaron M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sass","given":"CA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brownell","given":"AL","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jokivarsi","given":"KT.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kahn","given":"C Ronald","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"Kenneth K","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obesity","id":"ITEM-1","issue":"7","issued":{"date-parts":[["2012"]]},"page":"1519-1526","title":"Anatomical and Functional Assessment of Brown Adipose Tissue by Magnetic Resonance Imaging","type":"article-journal","volume":"20"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁴⁹","plainTextFormattedCitation":"149","previouslyFormattedCitation":"¹⁴⁹"},"properties":{"noteIndex":0},"schema":""}149- Healthy rats (n=9)- B3-adrenergic agonist (CL-316,243)- MION fMRI- 18F-FDG PET/CT- Figure 6 shows an immediate increase in iBAT blood volume upon BAT stimulation which is sustained for the duration of measurementKhanna et al. (2012)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.24118.Detecting","author":[{"dropping-particle":"","family":"Khanna","given":"Arjun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa T","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2012"]]},"page":"1285-1290","title":"Detecting Brown Adipose Tissue Activity with BOLD MRI in Mice","type":"article-journal","volume":"68"},"uris":[""]}],"mendeley":{"formattedCitation":"⁹⁹","plainTextFormattedCitation":"99","previouslyFormattedCitation":"⁹⁹"},"properties":{"noteIndex":0},"schema":""}99- Healthy mice (n=10)- Intraperitoneal injection of NE- BOLD fMRI- iBAT temperature- Figure 1: iBAT temperature increases a maximum of 5.5°C at 50 minutes after NE injection, and begins to decrease after 60 mins, reaching pre-injection levels around 140 mins- Figure 2B: iBAT is “fully stimulated” 1-2 minutes after NE injection (maximum BOLD signal change after roughly 40 minutes), and the signal slowly recovers over 60 minutes as NE is degraded in the bloodBranca et al. (2013)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0074206","author":[{"dropping-particle":"","family":"Branca","given":"Rosa T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Warren S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Auerbach","given":"Edward","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Khanna","given":"Arjun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Degan","given":"Simone","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ugurbil","given":"Kamil","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maronpot","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-1","issue":"9","issued":{"date-parts":[["2013"]]},"page":"e74206","title":"In Vivo Noninvasive Detection of Brown Adipose Tissue through Intermolecular Zero-Quantum MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶⁵","plainTextFormattedCitation":"65","previouslyFormattedCitation":"⁶⁵"},"properties":{"noteIndex":0},"schema":""}65- Healthy mice (n=4)- B3-adrenergic agonist (CL-316,243)- BATSCI MRI - Figure 6A shows the iBAT temperature following stimulation, which reaches a peak at 60 minutes and falls steadily thereafter- Figure 6B shows that iBAT BATSCI signal decreases immediately after stimulation, reaches a maximal signal change at around 50-60 minutes, and begins to risePanagia et al. (2016)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3557","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"27226402","abstract":"Recent studies have suggested that brown adipose tissue (BAT) plays an important role in obesity, insulin resistance and heart failure. The characterization of BAT in vivo, however, has been challenging. No technique to comprehensively image BAT anatomy and function has been described. Moreover, the impact on BAT of the neuroendocrine activation seen in heart failure has only recently begun to be evaluated in vivo. The aim of this study was to use MRI to characterize the impact of heart failure on the morphology and function of BAT. Mice subjected to permanent ligation of the left coronary artery were imaged with MRI 6 weeks later. T2 weighted MRI of BAT volume and blood oxygen level dependent MRI of BAT function were performed. T2 * maps of BAT were obtained at multiple time points before and after administration of the beta3 adrenergic agonist CL 316 243 (CL). Blood flow to BAT was studied after CL injection using the flow alternating inversion recovery (FAIR) approach. Excised BAT tissue was analyzed for lipid droplet content and for uncoupling protein 1 (UCP1) mRNA expression. BAT volume was significantly lower in heart failure (51 +/- 1 mm3 versus 65 +/- 3 mm3 ; p < 0.05), and characterized by a reduction in lipid globules and a fourfold increase in UCP1 mRNA (p < 0.05). CL injection increased BAT T2 * in healthy animals but not in mice with heart failure (24 +/- 4% versus 6 +/- 2%; p < 0.01), consistent with an increase in flow in control BAT. This was confirmed by a significant difference in the FAIR response in BAT in control and heart failure mice. Heart failure results in the chronic activation of BAT, decreased BAT lipid stores and decreased BAT volume, and it is associated with a marked decrease in ability to respond to acute physiological stimuli. This may have important implications for substrate utilization and overall metabolic homeostasis in heart failure. Copyright (c) 2016 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Panagia","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Y I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"H H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ernande","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chao","given":"W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwong","given":"K","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Scherrer-Crosbie","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sosnovik","given":"D E","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR Biomed","id":"ITEM-1","issue":"October 2015","issued":{"date-parts":[["2016"]]},"page":"978-984","title":"Functional and anatomical characterization of brown adipose tissue in heart failure with blood oxygen level dependent magnetic resonance","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁶","plainTextFormattedCitation":"106","previouslyFormattedCitation":"¹⁰⁶"},"properties":{"noteIndex":0},"schema":""}106- Healthy mice (n=5)- B3-adrenergic agonist (CL-316,243)- BOLD fMRI- Figure 2C shows a transient change in iBAT BOLD signal following stimulation, forming a sharp “spike” that lasts 4-6 “time points”Olsen et al. (2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.molmet.2017.02.006","author":[{"dropping-particle":"","family":"Olsen","given":"Jessica M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Csikasz","given":"Robert I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dehvari","given":"Nodi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lu","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sandstr?m","given":"Anna","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"?berg","given":"Anette I","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nedergaard","given":"Jan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stone-Elander","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bengtsson","given":"Tore","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Molecular Metabolism","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"page":"611-619","title":"Beta 3 Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰⁰","plainTextFormattedCitation":"100","previouslyFormattedCitation":"¹⁰⁰"},"properties":{"noteIndex":0},"schema":""}100- Healthy WT mice (n=?)- B3-adrenergic agonist (CL-316,243)- 18F-FDG PET/CT- Metabolic chamber- Figure 1C shows that upon stimulation, oxygen consumption increases transiently and appears to be reaching a maximum by 50 minutes post-injectionGarretson et al. 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(2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.08.006","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Simcox","given":"Judith","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geoghegan","given":"Gisela","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maschek","given":"John Alan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bensard","given":"Claire L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pasquali","given":"Marzia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miao","given":"Ren","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lee","given":"Sanghoon","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jiang","given":"Lei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huck","given":"Ian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kershaw","given":"Erin E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Donato","given":"Anthony J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Apte","given":"Udayan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Longo","given":"Nicola","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rutter","given":"Jared","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schreiber","given":"Renate","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zechner","given":"Rudolf","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cox","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Villanueva","given":"Claudio J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2017"]]},"page":"509-522.e6","publisher":"Elsevier","title":"Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁰¹","plainTextFormattedCitation":"101","previouslyFormattedCitation":"¹⁰¹"},"properties":{"noteIndex":0},"schema":""}101- WT male mice (n= 5)- Cold exposure (6 hours at 4°C)- Serum measurements- Figure 4 shows a time course of the following: FFAs increase to 1.1mM within 30 minutes of cold, whereas increases in serum LCACs occur at 3 hours (same with hepatic Cpt1b, which produced LCACs)Shin et al. (2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmet.2017.09.002","ISSN":"1550-4131","author":[{"dropping-particle":"","family":"Shin","given":"Hyunsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ma","given":"Yinyan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chanturiya","given":"Tatyana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cao","given":"Qiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Youlin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kadegowda","given":"Anil K G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jackson","given":"Rachel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rumore","given":"Dominic","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Xue","given":"Bingzhong","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shi","given":"Hang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gavrilova","given":"Oksana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yu","given":"Liqing","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cell Metabolism","id":"ITEM-1","issue":"11","issued":{"date-parts":[["2017"]]},"page":"1-14","publisher":"Elsevier Inc.","title":"Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice","type":"article-journal","volume":"26"},"uris":[""]}],"mendeley":{"formattedCitation":"¹¹⁵","plainTextFormattedCitation":"115","previouslyFormattedCitation":"¹¹⁵"},"properties":{"noteIndex":0},"schema":""}115- WT mice (n= 5)- B3-adrenergic agonist (CL-316,243)-BAT temperature- Oxygen consumption- Figures 3F and G show an immediate increase in core body temperature and oxygen consumption in response to injection in control animals, respectively 059118500194310057150000Figures 5A and D from Rachid et al. (2015)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/ijo.2015.94","ISSN":"0307-0565","author":[{"dropping-particle":"","family":"Rachid","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rodovalho","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Folli","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beltramini","given":"G C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Morari","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Amorim","given":"B J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pedro","given":"T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramalho","given":"A F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bombassaro","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tincani","given":"AJ","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chaim","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pareja","given":"JC","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Geloneze","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ramos","given":"CD","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cendes","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saad","given":"MJA","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Velloso","given":"LA","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"International Journal of Obesity","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2015"]]},"page":"1515-1522","publisher":"Nature Publishing Group","title":"Distinct regulation of hypothalamic and brown/beige adipose tissue activities in human obesity","type":"article-journal","volume":"39"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷³","plainTextFormattedCitation":"73","previouslyFormattedCitation":"⁷³"},"properties":{"noteIndex":0},"schema":""}73 which presents a reduction in fMRI signal within the first 5 minutes of cold exposure (CE) in lean but not obese subjects138430200752000Figure 4 from Stahl et al. (2016)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.25364","ISSN":"15222586","PMID":"27421080","abstract":"PURPOSE To evaluate the volume and changes of human brown adipose tissue (BAT) in vivo following exposure to cold using magnetic resonance imaging (MRI). MATERIALS AND METHODS The clavicular region of 10 healthy volunteers was examined with a 3T MRI system. One volunteer participated twice. A cooling vest that was circulated with temperature-controlled water was used to expose each volunteer to a cold environment. Three different water temperature phases were employed: baseline (23°C, 20 min), cooling (12°C, 90 min), and a final warming phase (37°C, 30 min). Temperatures of the water in the circuit, of the body, and at the back skin of the volunteers were monitored with fiberoptic temperature probes. Applying the 2-point DIXON pulse sequence every 5 minutes, fat fraction (FF) maps were determined and evaluated over time to distinguish between brown and white adipose tissue. RESULTS Temperature measurements showed a decrease of 3.8 ± 1.0°C of the back skin temperature, while the body temperature stayed constant at 37.2 ± 0.9°C. Focusing on the two interscapular BAT depots, a mean FF decrease of -2.9 ± 2.0%/h (P < 0.001) was detected during cold stimulation in a mean absolute volume of 1.31 ± 1.43 ml. Also, a correlation of FF decrease to back skin temperature decrease was observed in all volunteers (correlation coefficients: |r| = [0.51; 0.99]). CONCLUSION We found that FF decreases in BAT begin immediately with mild cooling of the body and continue during long-time cooling. J. Magn. Reson. Imaging 2016.","author":[{"dropping-particle":"","family":"Stahl","given":"Vanessa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Maier","given":"Florian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Freitag","given":"Martin T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floca","given":"Ralf O.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berger","given":"Moritz C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Umathum","given":"Reiner","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berriel Diaz","given":"Mauricio","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Herzig","given":"Stephan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weber","given":"Marc André","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dimitrakopoulou-Strauss","given":"Antonia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rink","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bachert","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ladd","given":"Mark E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nagel","given":"Armin M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"page":"369-380","title":"In vivo assessment of cold stimulation effects on the fat fraction of brown adipose tissue using DIXON MRI","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵⁶","plainTextFormattedCitation":"56","previouslyFormattedCitation":"⁵⁶"},"properties":{"noteIndex":0},"schema":""}56 which presents the time course of FF changes during thermoneutrality, cooling (white box), and warming in 10 subjects-2570283445510003126789300164500Figure 9 and Supplementary Figure 4 from McCallister et al. (2017)ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/mrm.26589","ISSN":"07403194","PMID":"28112821","abstract":"PURPOSE To assess the spatial correlation between MRI and 18F-fludeoxyglucose positron emission tomography (FDG-PET) maps of human brown adipose tissue (BAT) and to measure differences in fat fraction (FF) between glucose avid and non-avid regions of the supraclavicular fat depot using a hybrid FDG-PET/MR scanner. METHODS In 16 healthy volunteers, mean age of 30 and body mass index of 26, FF, R2*, and FDG uptake maps were acquired simultaneously using a hybrid PET/MR system while employing an individualized cooling protocol to maximally stimulate BAT. RESULTS Fourteen of the 16 volunteers reported BAT-positive FDG-PET scans. MR FF maps of BAT correlate well with combined FDG-PET/MR maps of BAT only in subjects with intense glucose uptake. The results indicate that the extent of the spatial correlation positively correlates with maximum FDG uptake in the supraclavicular fat depot. No consistent, significant differences were found in FF or R2* between FDG avid and non-avid supraclavicular fat regions. In a few FDG-positive subjects, a small but significant linear decrease in BAT FF was observed during BAT stimulation. CONCLUSION MR FF, when used in conjunction with FDG uptake maps, can be seen as a valuable, radiation-free alternative to CT and can be used to measure tissue hydration and lipid consumption in some subjects. Magn Reson Med, 2017. ? 2017 International Society for Magnetic Resonance in Medicine.","author":[{"dropping-particle":"","family":"McCallister","given":"Andrew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Le","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Burant","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Katz","given":"Laurence","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Branca","given":"Rosa Tamara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Magnetic Resonance in Medicine","id":"ITEM-1","issue":"November 2016","issued":{"date-parts":[["2017"]]},"title":"A pilot study on the correlation between fat fraction values and glucose uptake values in supraclavicular fat by simultaneous PET/MRI","type":"article-journal","volume":"00"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁴","plainTextFormattedCitation":"74","previouslyFormattedCitation":"⁷⁴"},"properties":{"noteIndex":0},"schema":""}74 Supplementary Material (Methods)Exclusion CriteriaTable SEQ Table \* ARABIC 9 - List of excluded medicationsClass of DrugsListDrugs affecting β-adrenergic receptorβ blockersAcebutolol (Sectral)Atenolol (Tenormin)Bisoprolol (Zebeta)Metoprolol (Lopressor, Toprol-XL)Nadolol (Corgard)Propranolol (Inderal LA, InnoPran XL) Asthma/COPD beta-adrenergic agonistsBambuterol (Bambec, Oxeol)Bitolterol mesylate (Tornalate)Clenbuterol (Dilaterol, Spiropent, Ventipulmin)Fenoterol (Berotec N)Formoterol (Foradil, Zenhale, Symbicort, Forpack Discair, Oxeze/Oxis)Isoprenaline/ Isoproterenol (Isuprel)Levosalbutamol (Levalbuterol, Xopenex)Metaproterenol (Alupent)Olodaterol (Striverdi)Pirbuterol (Maxair)ProcaterolSalbutamol (Albuterol, Ventolin)Salmeterol (Serevent Diskus)Terbutaline (Bricanyl)Vilanterol (Breo Ellipta, Relvar Ellipta)Others Mirabegron (Myrbetriq)Drugs associated with hepatic steatosis CorticosteroidsBetamethasone (Celestone)Budesonide (Pulmicort, Entocort EC)Cortone Acetate (Cortone)CotoloneDexamethasone (Decadron)Fludrocortisone (Florinef Acetate)Methylprednisolone (Medrol, Methylpred-DP)Prednisone (Bubbli-Pred, Deltasone, Prednicot, Prelone, Pediapred 5, Pms-prednisolone)Triamcinolone (Aristocort)TetracyclineDemeclocycline (Declomycin)Doxycycline (Doryx, Vibramycin)Minocycline (Dynacin, Minocin, Monodox)Oxytetracycline (Terramycin)Tetracycline (Achromycin)Tigecycline (Tygacil) OtherAmiodarone (Cordarone, Nexterone, Pacerone)L-asparaginase (Elspar)Methotrexate (Rheumatrex, Trexall)Tamoxifen(Nolvadex)Valproic acid (Depakote, Depakote ER, Depakote Sprinkle, Depakene, Depacon, Stavzor)Anti-hyperglycemic drugsAlpha-Glucosidase InhibitorAcarbose (Precose)Miglitol (Glyset)BiguanidesMetformin (Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet)Metformin combination drugsActoplus Met AvandametDuetactGlucovanceJanumetJentadueto KomboglyzeMetaglip PrandiMetDipeptidyl peptidase-4 (DPP-4) inhibitorAlogliptin (Nesina) Canagliflozin (Invokana)Dapagliflozin (Farxiga)Linagliptin (Tradjenta) Saxagliptin (Onglyza) Sitagliptin (Januvia)Glucagon-like peptideExenatide (Exendin-4, Byetta)Liraglutide (Victoza)Lixisenatide (Lyxumia)MeglitinidesRepaglinide (GlucoNorm, Prandin, NovoNorm)Nateglinide (Starlix) InsulinSulfonylureaChlorpropamide (Diabinese)Glimepiride (Amaryl)Glipizide (Glucotrol, Glucotrol XL)Glyburide (DiaBeta, Glynase PresTab, Micronase)TolbutamideYolazamide ThiazolidinedionesPioglitazone (Actos)Rosiglitazone (Avandia)HIV drugsHAARTAntidepressants, anxiolytic drugs, anti-psychotic drugs5-HT2 Receptor AntagonistsTrazodone (Desyrel, Oleptro, Trazorel, Trialodine, Trittico)5-HT3 Receptor AntagonistsVortioxetine (Brintellix, Trintellix)Dopamine Reuptake BlockerBupropion (Wellbutrin)MAOIs (Monoamine oxidase inhibitors)Isocarboxazid (Marplan)Phenelzine (Nardil)Selegiline (Emsam)Tranylcypromine (Parnate)SNRIs (Serotonin and norepinephrine reuptake inhibitors)Desvenlafaxine (Pristiq)Duloxetine (Cymbalta)Venlafaxine (Effexor XR)SSRIs (Selective serotonin reuptake inhibitor)Citalopram (Celexa)Escitalopram (Lexapro)Fuoxetine (Prozac)Fuvoxamine (Luvox)Paroxetine (Paxil)Sertraline (Zoloft)Tetracyclic AntidepressantMaprotiline (Teva-Maprotiline)Mirtazapine (Tera-Mirtazapine)Tricyclic medicationAmitriptyline (Elavil)Amoxapine (Asendin)Clomipramine (Anafranil)Desipramine (Norpramin)Doxepin (Silenor)Imipramine (Tofranil)Nortriptyline (Pamelor)Protriptyline (Vivactil)Trimipramine (Surmontil)Thyroid drugsAnti-thyroidMethimazole (Tapazole)Propylthiouracil (Propyl-Thyracil or PTU)Thyroidlevothyroxine (T4) (Levothroid, Levoxyl, Synthroid, Tirosint, Unithroid)liothyronine (T3) (Cytomel)liotrix (T3 and T4) (Thyrolar)Antiemetic (5HT3 antagonists)Dolasetron (Anzemet)Granisetron (Granisetron Hydrochloride)Ondansetron (Zofran)Palonosetron (Aloxi)Drugs associated with serotonin metabolismAmphetamineDextromethorphanMetoclopramideTable SEQ Table \* ARABIC 10 - List of excluded conditionsConditionsListDiseases associated with brown adipose tissue dysfunctionAdrenal gland disorder (i.e. pheochromocytoma)HibernomaDiseases associated with hepatic steatosis and liver disordersAbetalipoproteinemia Celiac disease Cystic fibrosisGalactosemiaGlycogen storage diseaseHemochromatosisHepatitis B or CHepatocellular carcinoma (HCC)HomocystinuriaInflammatory bowel diseaseLipodystrophyPolycystic liver diseaseTyrosinemiaWeber-Christian syndromeWilson’s diseaseList of serotonergic foods Foods to avoid 24-hours before each visit included:BananaWalnutPineapplePlumKiwiTomatoAvocadoVisit Timelines01229605Figure SEQ Figure \* ARABIC 11 – Initial Visit (McMaster University Medical Centre)0Figure SEQ Figure \* ARABIC 11 – Initial Visit (McMaster University Medical Centre)02616493Figure SEQ Figure \* ARABIC 12 – Time Course Visit (St. Joseph's Healthcare Hamilton)0Figure SEQ Figure \* ARABIC 12 – Time Course Visit (St. Joseph's Healthcare Hamilton)-684147901200028257500Data presented in this thesis are from the shaded regions in Figures 1 and 2 below.9525952500Figure SEQ Figure \* ARABIC 13 - Visual representation of the time course MRI session. Water was transported from the temperature-controlled baths to the water-perfused suit using insulated tubing. At the same time, fiber-optic temperature sensors recorded the temperature of the water entering and leaving the suit. All subjects wore a head and neck coil throughout the cold exposure in order to transmit the signal back to a computer which produced a raw image. Before they entered the scanner, all subjects were acclimatized at room temperature for 30 minutes and immediately following baseline FF measurements, cooling was started and scans were acquired every 5 minutes during the first 60 minutes of cooling, and every 15 minutes thereafter. Scans were then acquired every 5 minutes during the subsequent warming phase.MRI ParametersTable SEQ Table \* ARABIC 11 - MRI protocol parameters for IDEAL-IQPulse Sequence: IDEAL-IQParameterSCVLiverPatient EntryHead FirstFeet FirstPatient PositionSupineCoilHNS Head/Neck/ChestNeoCoil 32 Channel Torso ArrayOrientationAxialFlip angle43TEMin FullNumber of echoes6Echo Train Length 3Number of shots2Bandwidth 111.11Frequency axisBottom/UpPhase axisRight/LeftSpatial resolution (mm)1.48 x 1.481.33 x 1.33Acquired slice thickness (mm)48Imaging OptionsEDR, Fast, IDEAL, ARCStepwise procedure for image segmentationSCV BATThe following segmentation protocol for SCV BAT, which exhibited excellent inter-rater reliability (intraclass correlation coefficient of agreement >0.9 between three raters for both SCV BAT FF and segmentation volume) compared to previous studiesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/nbm.3444","ISBN":"1099-1492 (Electronic)\\r0952-3480 (Linking)","ISSN":"10991492","PMID":"26620447","abstract":"The supraclavicular fat depot is known for brown adipose tissue presence. To unravel adipose tissue physiology and metabolism, high quality and reproducible imaging is required. In this study we quantified the reliability and agreement of MRI fat fraction measurements in supraclavicular and subcutaneous adipose tissue of 25 adult patients with clinically manifest cardiovascular disease. MRI fat fraction measurements were made under ambient temperature conditions using a vendor supplied mDixon chemical-shift water-fat multi-echo pulse sequence at 1.5 T field strength. Supraclavicular fat fraction reliability (intraclass correlation coefficientagreement , ICCagreement ) was 0.97 for test-retest, 0.95 for intra-observer and 0.56 for inter-observer measurements, which increased to 0.88 when ICCconsistency was estimated. Supraclavicular fat fraction agreement displayed mean differences of 0.5% (limit of agreement (LoA) -1.7 to 2.6) for test-retest, -0.5% (LoA -2.9 to 2.0) for intra-observer and 5.6% (LoA 0.4 to 10.8) for inter-observer measurements. Median fat fraction in supraclavicular adipose tissue was 82.5% (interquartile range (IQR) 78.6-84.0) and 89.7% (IQR 87.2-91.5) in subcutaneous adipose tissue (p < 0.0001). In conclusion, water-fat MRI has good reliability and agreement to measure adipose tissue fat fraction in patients with manifest cardiovascular disease. These findings enable research on determinants of fat fraction and enable longitudinal monitoring of fat fraction within adipose tissue depots. Interestingly, even in adult patients with manifest cardiovascular disease, supraclavicular adipose tissue has a lower fat fraction compared with subcutaneous adipose tissue, suggestive of distinct morphologic characteristics, such as brown adipose tissue. Copyright (c) 2015 John Wiley & Sons, Ltd.","author":[{"dropping-particle":"","family":"Franssens","given":"Bas T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Eikendal","given":"Anouk L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leiner","given":"Tim","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Graaf","given":"Yolanda","non-dropping-particle":"van der","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Visseren","given":"Frank L J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hoogduin","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"NMR in Biomedicine","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016"]]},"note":"NULL","page":"48-56","title":"Reliability and agreement of adipose tissue fat fraction measurements with water-fat MRI in patients with manifest cardiovascular disease","type":"article-journal","volume":"29"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1371/journal.pone.0077907","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"19326203","PMID":"24205024","abstract":"There is a major resurgence of interest in brown adipose tissue (BAT) biology, particularly regarding its determinants and consequences in newborns and infants. Reliable methods for non-invasive BAT measurement in human infants have yet to be demonstrated. The current study first validates methods for quantitative BAT imaging of rodents post mortem followed by BAT excision and re-imaging of excised tissues. Identical methods are then employed in a cohort of in vivo infants to establish the reliability of these measures and provide normative statistics for BAT depot volume and fat fraction. Using multi-echo water-fat MRI, fat- and water-based images of rodents and neonates were acquired and ratios of fat to the combined signal from fat and water (fat signal fraction) were calculated. Neonatal scans (n = 22) were acquired during natural sleep to quantify BAT and WAT deposits for depot volume and fat fraction. Acquisition repeatability was assessed based on multiple scans from the same neonate. Intra- and inter-rater measures of reliability in regional BAT depot volume and fat fraction quantification were determined based on multiple segmentations by two raters. Rodent BAT was characterized as having significantly higher water content than WAT in both in situ as well as ex vivo imaging assessments. Human neonate deposits indicative of bilateral BAT in spinal, supraclavicular and axillary regions were observed. Pairwise, WAT fat fraction was significantly greater than BAT fat fraction throughout the sample (ΔWAT-BAT = 38 %, p<10(-4)). Repeated scans demonstrated a high voxelwise correlation for fat fraction (Rall = 0.99). BAT depot volume and fat fraction measurements showed high intra-rater (ICCBAT,VOL = 0.93, ICCBAT,FF = 0.93) and inter-rater reliability (ICCBAT,VOL = 0.86, ICCBAT,FF = 0.93). This study demonstrates the reliability of using multi-echo water-fat MRI in human neonates for quantification throughout the torso of BAT depot volume and fat fraction measurements.","author":[{"dropping-particle":"","family":"Rasmussen","given":"Jerod M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Entringer","given":"Sonja","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nguyen","given":"Annie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erp","given":"Theo G M","non-dropping-particle":"Van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guijarro","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oveisi","given":"Fariba","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Swanson","given":"James M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Piomelli","given":"Daniele","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wadhwa","given":"Pathik D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Buss","given":"Claudia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Potkin","given":"Steven G.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS ONE","id":"ITEM-2","issue":"10","issued":{"date-parts":[["2013"]]},"title":"Brown adipose tissue quantification in human neonates using water-fat separated MRI","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"^57,69","plainTextFormattedCitation":"57,69","previouslyFormattedCitation":"^57,69"},"properties":{"noteIndex":0},"schema":""}57,69, was established by Ong et al. (unpublished) and is described accordingly: Segmentation was performed in the axial plane using semi-automated and manual segmentation tools available within AnalyzePro (AnalyzeDirect, Overland Park, KS). Semi-automated techniques were used to circumvent processes that would normally be affected by operator bias or subjectivity, such as delineation of anatomical borders. The final protocol for SCV BAT consisted of five steps, which were repeated for each individual image:1. Application of fat mask: A fat mask, which was based on an image-specific threshold that was established via observed differences in MR intensities, was applied directly to the FF map (a post-processing product of the IDEAL sequence) at the C7-T1 disc. This process was used to isolate “adipose-like” tissues and exclude background noise from future consideration. The image at the C7-T1 disc was used as the reference for all participants as this anatomical level contains a relatively large amount of fat in the SCV region and consistently displayed reasonable fat-water contrast which is imperative for the accurate separation of adipose from non-adipose tissues.2. Application of FF threshold: A FF threshold from 30 to 100% was applied to the FF image. This ensured that only voxels within that defined range were included in the segmentation process (i.e. exclusion of “non-adipose tissue”). Ong et al. (unpublished) based this approach on published data in humans which suggests that SCV BAT occupies a wide range of FF values, and also through a series of protocol trials comparing this broad threshold (i.e. 30 to 100%) to a narrower threshold (i.e. 50 to 80%), wherein the former was more conservative in capturing cold-induces changes in FF. 3. Manual delineation of the SCV: A ROI was manually drawn over the SCV region using the “free-hand draw” tool (AnalyzeDirect, Overland Park, KS). Any adipose tissue between the C5/C6 and T1/T2 discs that was bound by the trapezius muscle posteriorly, the sternocleidomastoid muscle medially, and the clavicle bone inferiorly was included (see Figure 13 below).ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmri.24053","ISBN":"1522-2586 (Electronic) 1053-1807 (Linking)","ISSN":"10531807","PMID":"23440739","abstract":"PURPOSE To compare fat-signal fractions (FFs) and T2* values between brown (BAT) and white (WAT) adipose tissue located within the supraclavicular fossa and subcutaneous depots, respectively. MATERIALS AND METHODS Twelve infants and 39 children were studied. Children were divided into lean and overweight/obese subgroups. Chemical-shift-encoded water-fat magnetic resonance imaging (MRI) was used to quantify FFs and T2* metrics in the supraclavicular and adjacent subcutaneous adipose tissue depots. Linear regression and t-tests were performed. RESULTS Infants had lower supraclavicular FFs than children (P < 0.01) but T2* values were similar (P = 0.5). Lean children exhibited lower supraclavicular FFs and T2* values than overweight children (P < 0.01). In each individual infant and child, supraclavicular FFs were consistently lower than adjacent subcutaneous FFs. Supraclavicular T2* values were consistently lower than subcutaneous T2* values in children, but not in infants. FFs in both depots were positively correlated with age and weight in infants (P < 0.01). In children, they were correlated with weight and body mass index (BMI) (P < 0.01), but not age. Correlations between T2* and anthropometric variables existed in children (P < 0.01), but were absent in infants. CONCLUSION Cross-sectional comparisons suggest variations in FF and T2* values in the supraclavicular and subcutaneous depots of infants and children, which are potentially indicative of physiological differences in adipose tissue fat content, amount, and metabolic activity.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yin","given":"Larry","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Aggabao","given":"Patricia C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Magnetic Resonance Imaging","id":"ITEM-1","issue":"4","issued":{"date-parts":[["2013"]]},"page":"885-896","title":"Comparison of brown and white adipose tissues in infants and children with chemical-shift-encoded water-fat MRI","type":"article-journal","volume":"38"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷⁷","plainTextFormattedCitation":"77","previouslyFormattedCitation":"⁷⁷"},"properties":{"noteIndex":0},"schema":""}77 4. Erosion of ROI: The ROIs were then post-processed using a one-time 2D-dimensional 1x3 erode (jack structural element) to correct for any inherent partial volume effects in the images.5. Application of T2* mask: As the FF mask failed to discriminate between different types of “adipose-like” tissues within the SCV, which is heterogeneous in nature, a T2* mask was applied to the FF map. In particular, a T2* threshold between 2 and 25 msec isolated WAT-like voxels from BAT-like voxels. The upper bound of this T2* range was selected based on previous reports that identified ≥ 26 msec as being characteristic of muscles, fluids and white adipocytesADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.2214/AJR.12.8996","ISBN":"2122633255","ISSN":"0361803X","PMID":"23255760","abstract":"OBJECTIVE The purpose of this study was to characterize human brown adipose tissue (BAT) with chemical-shift water-fat MRI and to determine whether trends and differences in fat-signal fractions and T2(*) relaxation times between BAT and white adipose tissue (WAT) are consistently observed postmortem and in vivo in infants, adolescents, and adults. MATERIALS AND METHODS A postmortem body and eight patients were studied. A six-echo spoiled gradient-echo chemical-shift water-fat MRI sequence was performed at 3 T to jointly quantify fat-signal fraction and T2(*) in interscapular-supraclavicular BAT and subcutaneous WAT. To confirm BAT identity, biopsy and histology served as the reference in the postmortem study and PET/CT was used in five of the eight patients who required examination for medical care. RESULTS Fat-signal fractions and T2(*) times were lower in BAT than in WAT in the postmortem example and in seven of eight patients. With the exception of one case, nominal comparisons between brown and white adipose tissues were statistically significant (p < 0.05). Between subjects, a large range of fat-signal fraction values was observed in BAT but not in WAT. CONCLUSION We have shown that fat-signal fractions and T2(*) values jointly derived from chemical-shift water-fat MRI are lower in BAT than in WAT likely because of differences in cellular structures, triglyceride content, and vascularization. The two metrics can serve as complementary biomarkers in the detection of BAT.","author":[{"dropping-particle":"","family":"Hu","given":"Houchun H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Perkins","given":"Thomas G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chia","given":"Jonathan M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gilsanz","given":"Vicente","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Roentgenology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2013"]]},"page":"177-183","title":"Characterization of human brown adipose tissue by chemical-shift water-fat MRI","type":"article-journal","volume":"200"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶¹","plainTextFormattedCitation":"61","previouslyFormattedCitation":"⁶¹"},"properties":{"noteIndex":0},"schema":""}61. Whereas, the lower bound was selected based on the inherent limitations in IDEAL, which is unreliable at quantifying T2* values below 2 msec.Once SCV BAT FF values were generated for each image, results were combined on a spreadsheet and a time series plot was generated for each participant (Prism 7; GraphPad Software, La Jolla, CA, USA).Posterior Neck SAT The segmentation procedure for the posterior neck SAT was identical to what has been described for SCV BAT above, with two notable exceptions. First, posterior neck SAT was identified as a superficial tissue which was bound by the trapezius muscle anteriorly (Figure 13 below). Second, a T2* mask was not used as this tissue was presumed to be homogenous with respect to white adipocytes. Since this was not a primary outcome measure, only slices at the C5/C6, C6/C7 and C7/T1 discs were considered. 12712701421765Figure SEQ Figure \* ARABIC 14 - Axial Slice of the Lower Cervical Region00Figure SEQ Figure \* ARABIC 14 - Axial Slice of the Lower Cervical Region1275715-2702000In Figure 13, tissue bound by the sternocleidomastoid medially (green arrow) and trapezius posteriorly (red arrow) from the C5/C6 to T1/T2 discs was identified as SCV adipose tissue. “BAT” (teal) was then differentiated from “non-BAT” (yellow and blue) using a T2* mask. Cold-induced changes in SCV BAT were compared to the posterior neck SAT (orange).Pairwise comparisons for identifying time points of interestPairwise comparisons using a linear mixed model (LMM) with random slopes was selected due to its flexibility, robustness against missing data and unequally spaced time points, and ability to control for the inherent variations due to random effects (i.e. between subjects) when determining how much variation is due to a specified fixed effect, such as timeADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Gueorguieva","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krystal","given":"JH","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Archives of General Psychiatry","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2004"]]},"page":"310-317","title":"Move Over ANOVA: Progress in Analyzing Repeated-Measures Data and Its Reflection in Papers Published in the Archives of General Psychiatry","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"⁸³","plainTextFormattedCitation":"83","previouslyFormattedCitation":"⁸³"},"properties":{"noteIndex":0},"schema":""}83. First-order autoregressive (AR1) repeated covariance structure provided the lowest absolute Bayesian Information Criteria value (BIC) (see Table 12). BIC was used as a reference due to the fact that it penalizes a model fit based on the total number of parameters and number of subjects included in the analysisADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3758/s13428-012-0281-2","ISBN":"1342801202","author":[{"dropping-particle":"","family":"Oberfeld","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Franke","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Behavioural Research","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"page":"792-812","title":"Evaluating the robustness of repeated measures analyses: The case of small sample sizes and nonnormal data","type":"article-journal","volume":"45"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1186/1471-2288-12-33","ISSN":"1471-2288","author":[{"dropping-particle":"","family":"Vossoughi","given":"Mehrdad","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ayatollahi","given":"S M T","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Towhidi","given":"Mina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ketabchi","given":"Farzaneh","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC Medical Research Methodology","id":"ITEM-2","issue":"33","issued":{"date-parts":[["2012"]]},"page":"1-10","publisher":"BioMed Central Ltd","title":"On summary measure analysis of linear trend repeated measures data: performance comparison with two competing methods","type":"article-journal","volume":"12"},"uris":[""]}],"mendeley":{"formattedCitation":"^84,85","plainTextFormattedCitation":"84,85","previouslyFormattedCitation":"^84,85"},"properties":{"noteIndex":0},"schema":""}84,85. Two separate analyses were conducted using the above model specifications for SCV BAT: one with time point 1 (i.e. 0 minutes) as the reference, and one with time point 21 (i.e. 180 minutes) as the reference. The same analysis procedure was repeated for the posterior neck SAT, but only time point 1was used as the reference. A Bonferroni correction was employed to minimize the implications of multiple comparisons error.Table SEQ Table \* ARABIC 12 - Linear mixed model selection summaryFF REDUCTIONREPEATED COVARIANCE TYPERANDOM COVARIANCE TYPEBIC RESULTCOMPOUND SYMMETRY810.492ARH1790.819ARH1 HETEROGENEOUS1021.902TOEPLITZ917.038Quadratic Modeling of SCV BAT FFA random-intercept multilevel regression model with the lowest BIC value (as above) was used to evaluate the relationship between BAT FF (dependent variable) and time (independent variable). Such model accounts for the intra-class correlation (ICC) due to multiple measurements within subjects, and for random effects between subjectsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1111/j.1467-985X.2007.00509.x","author":[{"dropping-particle":"","family":"Steele","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of the Royal Statistical Society","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2008"]]},"page":"5-19","title":"Multilevel Models for Longitudinal Data","type":"article-journal","volume":"171"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁵⁰","plainTextFormattedCitation":"150","previouslyFormattedCitation":"¹⁵⁰"},"properties":{"noteIndex":0},"schema":""}150. Due to the perceived quadratic relationship between BAT FF and time, the following model was used: FF%=b0+b1time+b2time2+ε where b0is the model intercept, b1is the slope for the linear component, b2is the slope for the quadratic component, and ε is unobserved random error.Supplementary Material (Results)Individual Time Course Plots (FF reduction)COMPLETED 180 MINUTES OF COLD EXPOSURE11112567310001003306731000111125996950094615996950011112512255500135890122555001111252349500114300234950016386361270000COMPLETED > 60 TO < 180 MINUTES OF COLD EXPOSURE17526043778002254254127500COMPLETED 60 MINUTES OF COLD EXPOSURE175260113665002254251085850016455099876100Individual Time Course Plots (Absolute Change)ALL787401162050021907511620500 COMPLETED 180 MINUTES OF COLD EXPOSURE7874076200002190757620000-76201009650017907010096500-76202413000172720241300016167851270000COMPLETED > 60 TO < 180 MINUTES OF COLD EXPOSURE-184156985000-53797048500COMPLETED 60 MINUTES OF COLD EXPOSURE-18415781050014605781050015415561460500817693848100031181921329690Figure SEQ Figure \* ARABIC 15 - T2* reduction during cooling0Figure SEQ Figure \* ARABIC 15 - T2* reduction during coolingTime course of change in T2* during Cooling1834187675880Figure SEQ Figure \* ARABIC 16 – Changes in SCV BAT FF (left) and posterior neck SAT FF (right) during cooling among those who completed the full 3-hour exposure. Time course plots of FF reduction (A,D), AUC for 30 minute intervals (B,E), and slope for 30 minute intervals (C,F). Data are presented as mean±SD. N=7.00Figure SEQ Figure \* ARABIC 16 – Changes in SCV BAT FF (left) and posterior neck SAT FF (right) during cooling among those who completed the full 3-hour exposure. Time course plots of FF reduction (A,D), AUC for 30 minute intervals (B,E), and slope for 30 minute intervals (C,F). Data are presented as mean±SD. N=7.-5866449657000Time course of change among individuals who completed the full duration of cooling (n=7)Tabular Output from the Pairwise ComparisonsSCV BAT FFTable SEQ Table \* ARABIC 13 - Pairwise comparisons using LMM with 0 minutes used as the reference (SCV BAT)REFERENCE POINT (J)COMPARISON POINT (I)NMEAN DIFFERENCE (I-J)P-VALUE0 MIN5MIN11-1.260.09710MIN12-1.600.007*15MIN12-1.920.001*20MIN11-1.880.002*25MIN10-2.29<0.001*30MIN12-1.820.004*35MIN10-2.54<0.001*40MIN9-1.920.008*45MIN12-2.93<0.001*50MIN10-2.73<0.001*55MIN9-3.18<0.001*60MIN11-3.21<0.001*75MIN9-3.86<0.001*90MIN9-4.56<0.001*105MIN8-4.45<0.001*120MIN8-3.97<0.001*135MIN8-4.76<0.001*150MIN7-4.76<0.001*165MIN7-4.28<0.001*180MIN7-3.81<0.001**Denotes statistical significance at the 0.05 levelTable SEQ Table \* ARABIC 14 - Pairwise comparisons using LMM with 180 minutes used as the reference (SCV BAT)REFERENCE POINT (J)COMPARISON POINT (I)NMEAN DIFFERENCE (I-J)P-VALUE180 MIN0MIN123.81<0.001*5MIN112.540.004*10MIN122.210.019*15MIN121.890.08120MIN111.920.07425MIN101.52>0.10030MIN121.980.042*35MIN101.26>0.10040MIN91.880.08445MIN120.88>0.10050MIN101.08>0.10055MIN90.62>0.10060MIN110.59>0.10075MIN9-0.06>0.10090MIN9-0.75>0.100105MIN8-0.64>0.100120MIN8-0.16>0.100135MIN8-0.95>0.100150MIN7-0.95>0.100165MIN7-0.48>0.100*Denotes statistical significance at the 0.05 levelTime course of change in posterior neck SAT FFTable SEQ Table \* ARABIC 15 - Summary of individual cold-induced changes in posterior neck SAT FFSUBJECTPRE-COLD FF (%)MAX FF REDUCTION (%)TIME TO MAX FF REDUCTION (min)FF REDUCTION @ END OF COLD (%)DURATION OF COLD (min)185.102.731500.91180277.990.2675-0.47180387.190.711200.3180489.001.4450.9760589.430.89550.5260669.342.67150.23135783.43.141803.14180876.422.42200.8960969.530.07150-0.71801080.543.31152.71901166.883.155-0.061801275.003.521803.52180Table SEQ Table \* ARABIC 16 - Pairwise comparisons using LMM with 0 minutes used as the reference (posterior neck SAT)REFERENCE POINT (J)COMPARISON POINT (I)NMEAN DIFFERENCE (I-J)P-VALUE0 MIN5MIN110.14>0.10010MIN12-0.10>0.10015MIN12-0.50>0.10020MIN11-0.43>0.10025MIN10-0.67>0.10030MIN12-0.38>0.10035MIN10-0.52>0.10040MIN9-0.63>0.10045MIN12-0.43>0.10050MIN10-0.45>0.10055MIN9-0.76>0.10060MIN11-0.44>0.10075MIN9-0.66>0.10090MIN9-0.97>0.100105MIN8-1.260.074120MIN8-1.18>0.100135MIN8-0.67>0.100150MIN7-1.11>0.100165MIN7-0.92>0.100180MIN7-1.16>0.100*Denotes statistical significance at the 0.05 levelInvestigating if participant characteristics are related to the pattern of cold-induced changeComparing those who withstood the entire duration of cooling and those who did not53340097790000Environmental Factors574040201295Figure SEQ Figure \* ARABIC 17 - Jitter plots of ambient temperature during the time course cold exposure visit (left) and outdoor temperature one hour before the time course cold exposure visit (right) in individuals who completed <60 minutes, >60,<180 minutes, and 180 minutes of cold00Figure SEQ Figure \* ARABIC 17 - Jitter plots of ambient temperature during the time course cold exposure visit (left) and outdoor temperature one hour before the time course cold exposure visit (right) in individuals who completed <60 minutes, >60,<180 minutes, and 180 minutes of coldMRI room temperature, which can augment the effects of a cold exposure delivered via a water-perfused suit, was similar among all 12 participants (left panel). Furthermore, outdoor temperature might allude to an individual’s a priori state of cold acclimationADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Ooijen","given":"A.M.J.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marken Lichtenbelt","given":"Wouter D.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Steenhoven","given":"A.A.","non-dropping-particle":"van","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Westerterp","given":"K.R.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Physiology & Behavior","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2004"]]},"page":"545-553","title":"Seasonal changes in metabolic and temperature responses to cold air in humans","type":"article-journal","volume":"82"},"uris":[""]}],"mendeley":{"formattedCitation":"¹⁵¹","plainTextFormattedCitation":"151","previouslyFormattedCitation":"¹⁵¹"},"properties":{"noteIndex":0},"schema":""}151. However given the large variability of outdoor temperature recorded near the time course acquisition visits, especially among those who endured the full duration of cold, this was also likely not a contributing factor to the observed findings.-635338455Figure SEQ Figure \* ARABIC 18 - Jitter plots of BMI (left), LMI (middle) and % total body fat (right) in individuals who completed <60 minutes, >60,<180 minutes, and 180 minutes of cold. Data are presented as median±IQR.00Figure SEQ Figure \* ARABIC 18 - Jitter plots of BMI (left), LMI (middle) and % total body fat (right) in individuals who completed <60 minutes, >60,<180 minutes, and 180 minutes of cold. Data are presented as median±IQR.Body Composition -260985593476Although BMI was comparable between groups (left panel), % body fat of those who endured only the first hour of cold exposure were either outside or approaching the upper IQR of the other two groups (right panel). In other words, those with a higher % total body fat appeared to tolerate cold the shortest. Complementary to this finding, those who withstood cold the longest tended to have a higher LMI which might allude to a heightened ability to undergo shivering thermogenesis, a dominant source of cold-induced heat productionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1113/jphysiol.2014.283598","ISBN":"0022-3751","ISSN":"1469-7793","PMID":"25384777","abstract":"KEY POINTS: Both brown adipose tissue (BAT) and skeletal muscle activation contribute to the metabolic response of acute cold exposure in healthy men even under minimal shivering. Activation of adipose tissue intracellular lipolysis is associated with BAT metabolic response upon acute cold exposure in healthy men. Although BAT glucose uptake per volume of tissue is important, the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized. ABSTRACT: Cold exposure stimulates the sympathetic nervous system (SNS), triggering the activation of cold-defence responses and mobilizing substrates to fuel the thermogenic processes. Although these processes have been investigated independently, the physiological interaction and coordinated contribution of the tissues involved in producing heat or mobilizing substrates has never been investigated in humans. Using [U-(13) C]-palmitate and [3-(3) H]-glucose tracer methodologies coupled with positron emission tomography using (11) C-acetate and (18) F-fluorodeoxyglucose, we examined the relationship between whole body sympathetically induced white adipose tissue (WAT) lipolysis and brown adipose tissue (BAT) metabolism and mapped the skeletal muscle shivering and metabolic activation pattern during a mild, acute cold exposure designed to minimize shivering response in 12 lean healthy men. Cold-induced increase in whole-body oxygen consumption was not independently associated with BAT volume of activity, BAT oxidative metabolism, or muscle metabolism or shivering intensity, but depended on the sum of responses of these two metabolic tissues. Cold-induced increase in non-esterified fatty acid (NEFA) appearance rate was strongly associated with the volume of metabolically active BAT (r = 0.80, P = 0.005), total BAT oxidative metabolism (r = 0.70, P = 0.004) and BAT glucose uptake (r = 0.80, P = 0.005), but not muscle glucose metabolism. The total glucose uptake was more than one order of magnitude greater in skeletal muscles compared to BAT during cold exposure (674 ± 124 vs. 12 ± 8 μmol min(-1) , respectively, P < 0.001). Glucose uptake demonstrated that deeper, centrally located muscles of the neck, back and inner thigh were the greatest contributors of muscle glucose uptake during cold exposure due to their more important shivering response. In summary, these results demonstrate for the first time that the increase in plasma NEFA appearance from WA…","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Labbé","given":"Sébastien M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of physiology","id":"ITEM-1","issue":"3","issued":{"date-parts":[["2015"]]},"page":"701-14","title":"Contributions of white and brown adipose tissues and skeletal muscles to acute cold-induced metabolic responses in healthy men.","type":"article-journal","volume":"593"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1038/ncomms14146","ISSN":"2041-1723","PMID":"28134339","author":[{"dropping-particle":"","family":"Blondin","given":"Denis P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tingelstad","given":"Hans C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Noll","given":"Christophe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Frisch","given":"Frédérique","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Phoenix","given":"Serge","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guérin","given":"Brigitte","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Turcotte","given":"?ric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Richard","given":"Denis","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Haman","given":"Fran?ois","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carpentier","given":"André C.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"note":"NULL","page":"14146","title":"Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men","type":"article-journal","volume":"8"},"uris":[""]}],"mendeley":{"formattedCitation":"^11,114","plainTextFormattedCitation":"11,114","previouslyFormattedCitation":"^11,114"},"properties":{"noteIndex":0},"schema":""}11,114. Indices of BAT Activity508000104775000655955646430Figure SEQ Figure \* ARABIC 19 - Jitter pots summarizing total AUC at 10 minutes (left) and 60 minutes (right)00Figure SEQ Figure \* ARABIC 19 - Jitter pots summarizing total AUC at 10 minutes (left) and 60 minutes (right)AUC calculations within the first 60 minutes of cold exposure were visually compared between groups. Figure 18 presents an expected increase in AUC over the first hour of cold exposure regardless of length of cold exposure endured. However, the distribution of AUC within and between groups did not appear to change over this time, suggesting that it might not feasible to differentiate between individuals who endured varying lengths of cold based solely on patterns of SCV BAT FF.Table SEQ Table \* ARABIC 17 - Tabular output comparing those who completed the full duration of cooling and those who did not. Values presented as median (min,max)60 MINS (n=3)>60, <180 MINS (n=2)180 MINS (n=7)COVARIATESBMI (kg/m2)27.0 (24.4, 28.9)22.7 (19.8, 25.5)23.7 (21.0, 28.0)% TOTAL FAT37.1 (21.7, 38.4)21.7 (21.2, 22.2)21.1 (15.6, 30.9)AMBIENT TEMP20.5 (20.1, 20.6)20.5 (20.3, 20.6)20.4 (19.2, 21.0)OUTDOOR TEMP-0.4 (-10.6, 9.6)2.6 (1.9, 3.2)9.6 (-12.2, 18.9)INDICES10 MIN AUC8.95 (3.18, 22.08)12.14 (4.48, 19.8)7.0 (-3.6, 27.78)25 MIN AUC41.63 (22.5, 62.95)38.18 (7.93, 68.43)25.48 (5.55, 57.10)35 MIN AUC63.58 (31.2, 142.1)63.26 (18.7, 107.83)37.5 (18.9, 79.85)45 MIN AUC87.43 (40.8, 205.35)88.35 (23.68, 153.03)57.2 (41.78, 116.03)60 MIN AUC169.5 (58.5, 258.6)126.5 (36.9, 216.0)110.4 (72.9, 181.0)Relating indices of BAT activity with indices of body composition at time points of interestTable SEQ Table \* ARABIC 18 - P-values corresponding to each Spearman rho value identified in Figure 8 aboveAUCBMI% BODY FATFF REDUCTIONBMI% BODY FAT180 MIN AUC0.048*0.034*180 MIN REDUC0.003*0.11090 MIN AUC0.048*0.034*90 MIN REDUC0.1670.08860 MIN AUC0.007*0.034*60 MIN REDUC0.1390.06610 MIN AUC0.048*0.39610 MIN REDUC0.2000.200Relating indices of BAT activity with indices of body composition at all time points0254000Figure SEQ Figure \* ARABIC 20 - Time course of Spearman correlation coefficients for the relationships between indices of body composition (i.e. BMI (orange), % body fat (blue), and LMI (green)) and FF reduction (A) and AUC (B). The magnitude and direction of each rho value is presented. *denotes statistical significance at p<0.05. N=7 in each association unless specified otherwise. 0359410Figure SEQ Figure \* ARABIC 21 - T2* reduction during warming0Figure SEQ Figure \* ARABIC 21 - T2* reduction during warming067500500Time course of T2* reduction during warming-5080365760Figure SEQ Figure \* ARABIC 22 - Proposed model for time course of fuel use during BAT activation00Figure SEQ Figure \* ARABIC 22 - Proposed model for time course of fuel use during BAT activation-63567246500Supplementary Material (Discussion)BIBLIOGRAPHYADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1 Festuccia WT, Blanchard P-G, Deshaies Y. Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARγ. Front Endocrinol (Lausanne) 2011; 2: 1–6.2 Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293: 444–452.3 Gilsanz V, Hu HH, Kajimura S. 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