The Effects of Biopsychology on Appetite and Obesity



The Effects of Biopsychology on Appetite and Obesity

Megan Donley

Kent State University

Trumbull/Warren Campus

PSYC 41363 Biopsychology

Dr. Richard Vardaris

Submitted for Week 15

Obesity is a topic of growing concern in our modern society. Listed by many sources as the number one public health issues, research into obesity is at an all time high. Defined as “The condition of being obese; increased body weight caused by excessive accumulation of fat”[1], obesity can mean a range of weights that are determined to be unhealthy. Although an individual clinical condition, obesity has been linked to a number of more serious diseases, including cardiovascular disease, type 2 diabetes, sleep apnea, as well as renal and liver failure.

Neurobiological research into obesity was limited until the discovery of leptin in 1994 by Jeffrey Friedman. Since this discovery several other hormonal mechanisms have been explored, including research into ghrelin, orexin, PYY 3-36, cholecystokinin, adiponectin, adipose storage mechanisms and the development of insulin resistance.

The research I have chosen to present today includes several aspects of the pharmacological treatment of appetite and obesity, as well as several studies looking at the change in diet type, fats versus proteins, liking versus wanting. Any research into obesity and appetite must also take into account the changing norms of culture and society that have helped spread the obesity pandemic, including the shift in our daily lives from physical labor, to our current standard, which is considerably less physically demanding. Changes in diet are also to be considered as part of the obesity prevalence.

Overall I think I will have presented a thorough and comprehensive look at where research into biopsychological effects and possible pharmacological treatment of obesity and appetite is heading.

Traditionally, weight loss drugs have been focused on reducing energy intake, or appetite suppressants. However, recent research is showing that obesity is not just a result of gluttony or over consumption, but a combination of complex biological and psychological processes. The expression of appetite can be seen as having three underlying domains: psychological events, peripheral physiology and metabolic events, and neurochemical and metabolic interactions with the Central Nervous System (Halford et al., 2003). All three of these domains must act in conjunction to induce the expression of appetite.

[pic]The psychobiological expression of appetite and the three levels of operation, i. Psychological and behavioral events, ii.Physiological and metabolic operations, iii. Neurochemical and metabolic interactions within the CNS (Abbreviations: 5-HT, Serotonin; AA,Amino acids; AgRP, Agouti Related Peptide; CART, Cocaine and Amphetamine regulated transcript; CCK, Cholecystokinin; CRF,

Corticotropin Releasing Factor; FFA, Free Fatty Acids; GI, Gastro intestinal; GLP-1, Glucagon Like peptide-1; GRP, Gastric Releasing

Peptide; MC, Melanocortin; NPY, Neuropeptide Y; T/LNAA, NTS, Nucleus Tractus Solitarius; T/LNAA, Tryptophan Large Neutral AminoAcids ratio).

©Halford, J. C. G. (2003). The Psychopharmacology of Appetite: Targets for Potential Anti-Obesity Agents. Current Medicinal Chemistry - Central Nervous System Agents, 3(4), 283-310.

The assessment of appetite begins with the Central Nervous System (CNS). There are a variety of structures in the CNS, coupled with a multitude of signals that are responsible for assessing the physical need for energy, beginning or ending conscious feelings of hunger, and initiating the appropriate behavioral action. Information that modulates appetite reaches the CNS one of three ways: signals from the periphery, signals from specific receptors and from substances that directly act upon the CNS across the blood brain barrier.

Past theories of appetite control focused on two opposing hypothalamic centers, the lateral hypothalamus (LH) and the ventral medial hypothalamus (VMH). However, later studies have shown many other areas to be involved in appetite control including: the Paraventricular nucleus (PVN), Arcuate nucleus (ARC), Nucleus Accumbens (NAc) and Amygdala, the Posterior Hypothalamus and the Dorsomedial Hypothalamus (Halford et al.).

Limbic sites that function as a part of appetite are the NTS/AP (Nucleus of the Solitary Tract/ Area Postrema) a tract that runs from the brain stem to the limbic system and is responsible for relaying vagal afferent signals from the gastrointestinal tract and the liver to the hypothalamus. Additionally, receptors sensitive to the levels of nutrients circulating in the body are located here, as well as sensory information from the mouth (taste) which is relayed to the cortex through the NTS via the cranial nerves.

“With the discovery of numerous biological systems underpinning the natural control of food intake, many potential useful molecular targets for drug action have been revealed,”[2] (Halford et al.).

Our experience with appetite comes mainly through our relationship with food. The processes of consumption, digestion and metabolism, generate our feelings of hunger and satiety, which then determines our future behavior. These behaviors range from meal initiation and meal termination to the length and duration of between meal intervals. Hunger motivates us to seek food, while feelings of satiety bring the meal period to an end. The level of satiety dictates not only meal size, but the interval between meals.

There are several types of drug research going on that focus on different types of peripheral information. Episodic (short term) factors, which are released in response to food in the gastrointestinal tract have been implicated in processes involving within meal satiation and maintaining the feeling of satiety longer. Specific macronutrients are particularly effective in this area, including factors like Cholecystokinin (CCK), Glucagon-Like Peptide (GLP)-1, Enterostatin, Gastrin Releasing Factor (GRF)/ Bombesin-Like Peptides (BLP) and Apoliproprotien (pro)-A-IV (Halford et al.).

Another important aspect affecting episodic hunger is Ghrelin. Discovered in 1999 by Masayasu Kojima[3], Ghrelin is an important hormone involved in appetite stimulation. Considered to be the opposite of leptin, ghrelin levels increase before mealtime and decrease after meals. Ghrelin also plays a role in the release of growth hormone from the anterior pituitary gland (Akio Inui, 2004). Some bariatric procedures have reduced the amount of ghrelin, causing satiation before it would normally occur.

Leptin is the counterpart to ghrelin, and is a protein hormone responsible for the regulation of energy intake and expenditure, including appetite and metabolism. Leptin is the initial hormone that led to increased research into biopsychological factors associated with obesity, and interacts with the ventral medial nucleus of the hypothalamus, mentioned previously.

[pic]

©AKIO INUI, AKIHIRO ASAKAWA, CYRIL Y. BOWERS, GIOVANNI MANTOVANI, ALESSANDRO LAVIANO, MICHAEL M. MEGUID, and MINEKO FUJIMIYA

Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ

FASEB J. 18: 439-456.

A very small group of humans posses the homozygous mutation for leptin, leading to a constant demand for food, which then results in severe obesity. However this condition is easily treated by dosing with recombinant human leptin (Akio Inui). Leptin is also regulated (downward) by melatonin, which will be discussed later.

Beyond the episodic signals of the CNS, information is also received from the energy reserves, otherwise known as the adipose tissue or fat. This information is referred to as the tonic, or long term peripheral information. The ability to maintain a set body weight over time gives rise to the theories of lipostatic and ponderostatic energy regulation. Depletion or repletion of energy reserves would form a separate class of tonic appetite modulators. These modulators could inhibit or augment the hypophagic episodic signals generated on a meal by meal basis (Halford et al.). There are several such substances including: satietin, adispin, cytokines, resistin and adiponectin (ARCP-30).

Cytokines are generally produced in response to immune stimulation, but their effects are not limited to those of the immune system. Operating as part of an acute anorexic response to illness, many cytokines have been shown to inhibit food intake. While this seems to suggest that the brain can respond to significant changes in the cytokine levels circulating in the body, limited success has been found in the lab. Only the interleukin-6 type CNTF (cilliary neurotrophic factor) in the form of Axokine has had significant success at reducing the food intake of laboratory rats, and reducing their overall body weight by up to 29% in only seven days (Halford et al.).

Aminergic drugs have long been recognized for their effects on food intake and the reduction of body weight. Drugs ranging from amphetamine, mazindol, phentermine, phenylpropanolamine (PPA), dietyhlpropion, and fenfluramine (which in combination with phentermine was marketed as Fen-Phen and later recalled). Phentermine itself is still available under a number of brand names.

For a long time the only pharmaceutical treatment for obesity was noradrenaline (NA), the noradrenergic (and dopaminergic) agent of amphetamine. Because the actions of noradrenaline on food intake are paradoxical at best, depending largely on the location and type of receptor stimulated, research in this area is not at the forefront at this time. Recent studies into the side effects and the epidemic of abuse problems have effectively eliminated the amphetamine class as a useful compound.

Phenylpropanomine (PPA) is one agent that is still widely used in practice as well as remaining available directly to those who wish to lose weight. The hypophagic effects of PPA are what make it different than other forms of amphetamine. PPA has also been shown effective in reducing the weight gain associated with some psychotropic drugs, such as clozapine, commonly used to treat refractory schizophrenia. Remaining to be seen is whether PPA also has a thermogenic effect, which would increase its weight loss potential.

Sibutramine is one of the most widely distributed drugs for the treatment of obesity. Sibutramine shares characteristics with several other types of drugs, including NA, and 5-HT (or serotonin) activity. Sibutramine inhibits the reuptake of neurotransmitters instead of stimulating their release, and has no obvious effect on dopaminergic function. The combined serotonergic and noradrenergic reuptake inhibitor is commonly referred to as the SNRI class of drugs. Other SNRI’s include Venlafaxine, which has been the least studied for obesity and Duloxetine, but these should not be confused with SSRI (Selective Serotonin Reuptake Inhibitor) drugs (Blundell & Halford, 1998).

Originally developed as an antidepressant, during its initial clinical trials the dosage dependent body weight reduction of sibutramine was first noted. The therapeutic effects were confirmed when six different dosages resulted in significant weight loss by obese individuals over a twenty four week period.[4] This sibutramine induced weight loss has also been shown to improve glycemic control in obese type two diabetics.[5]

Recent testing done on sibutramine class drugs has indicated that while producing effects on behavior and appetite, the changes occur at dosages that do not induce motor activity as seen with amphetamine drugs. Long term studies have not yet been completed to determine if long term weight loss is feasible with this type of drug.

Of the most studied monoamines, serotonin, or 5-HT has been the most closely linked with satiation and the state of satiety.[6]

[pic]

©Blundell, J. E., & Halford, G. (1998). Serotonin and appetite regulation: Implications for the pharmacological treatment of obesity. CNS Drugs, 9(6), 473-495.

“First described over twenty years ago, the serotonin system plays an important role in the central regulation of food intake,” (Appolinario, Bueno & Coutinho, 2004). Present data about serotonin and how it affects the appetite indicate that the most directly implicated receptors are the presynaptic 5-HT1A and postsynaptic 5-HT1B and 5-HT2C receptors (see illustration on page 10) (Blundell& Halford). Most commonly, selective receptor antagonists are used to suppress the anoretic action of serotonin releasers or reuptake inhibitors.

Recent research has also shown a relationship between the administration of serotonin and the food macronutrient selection of participants. While initial studies found serotonin to influence carbohydrate selection, recent animal studies have shown it to influence fat selection (Appolinario).

Fluoxetine is another SSRI drug that has been extensively studied in reference to weight loss. Human trials have shown it to be effective in reducing food intake and accompanying reductions in hunger. A reduction in eating occasions was also noted (Appolinaro). Specific studies of fluoxetine have not demonstrated any action on macronutrient selection. Studies done on patients with depression reported weight loss as an adverse effect, and many short and long term studies have been done to establish a regular pattern of weight loss. In the long term studies that have been completed there is some question as to the efficacy of fluoxetine in long term weight loss, and long term weight management. Goldstein et al.[7] conducted a fifty two week, multi location, placebo controlled trial in four hundred fifty eight depressed obese patients, the weight loss was statistically significant at week twenty, but was not by week fifty two (Appolinaro).

To list every drug that is currently being evaluated for its weight loss potential would take years, instead a brief overview of the most significant areas of research and the importance of several key findings are discussed. While the outlook is certainly hopeful for a future drug that meets all the necessary elements of an appetite suppressant or anti-obesity drug, such as: halting pre-drug weight gain, preventing weight regain, selectively reducing adipose tissue, marked improvements in health, marked improvements in quality of life, with few side effects, and avoiding aversive side effects (Halford et al.).

The health of the world, especially of the United States relies on some means to prevent obesity, regain and retain healthy body weights. Any researcher will tell you that the magic answer isn’t going to be found in pill form, but in combination with lifestyle change, psychological care and motivation, there can be long term success.

References

Akio Inui, Akihro Asakawa, Cyril Y. Bowers, Giovanni Mantovani, Alessandro

Laviano, Michael M. Meguid, and Mineko Fujimya. Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ FASEB J. 18: 439-456

Appleton, K. M., Rogers, P. J.,  & Blundell, J. E. (2004). Effects of a sweet and a nonsweet lunch on short-term appetite: Differences in female high and low consumers of sweet/low-energy beverages. Journal of Human Nutrition and Dietetics, 17(5), 425-434.

Appolinario, J. C., Bueno, J. R.,  & Coutinho, W. (2004). Psychotropic Drugs in the Treatment of Obesity: What Promise? CNS Drugs, 18(10), 629-651.

Black, David R., and William E. Threlfall. "Partner Weight Status and Subject Weight Loss:Implications for Cost-Effective Programs and Public Health." Addictive Behaviors 14 (1989): 279-289.

Blundell, J. E., &  Halford, G. (1998). Serotonin and appetite regulation: Implications for the pharmacological treatment of obesity. CNS Drugs, 9(6), 473-495.

Cotton, J. R., Burley, V. J., Weststrate, J. A.,  & Blundel, J. E. (2007). Dietary fat and appetite: Similarities and differences in the satiating effect of meals supplemented with either fat or carbohydrate. Journal of Human Nutrition and Dietetics, 20(3), 186-199.

Finlayson, G., King, N.,  & Blundell, J. E. (2007). Liking vs. wanting food: Importance for human appetite control and weight regulation. Neuroscience & Biobehavioral Reviews, 31(7), 987- 1002.

Halford, J. C. G. (2003). The Psychopharmacology of Appetite: Targets for Potential Anti-Obesity Agents. Current Medicinal Chemistry - Central Nervous System Agents, 3(4), 283-310.

Rogers, P. J., Carlyle, J., Hill, A. J.,  & Blundell, J. E. (1988). Uncoupling sweet taste and calories: Comparison of the effects of glucose and three intense sweeteners on hunger and food intake. Physiology & Behavior, 43(5), 547-552.

Rodgers, Peter J., and Andrew J. Hill. "Breakdown of Dietary Restraint Following Mere Exposure to Food Stimuli: Interrelationships Between Restraint, Hunger, Salivation, and Food Intake." Addictive Behaviors 14 (1989): 387-397.

"Obesity." MedLine Plus. 10 Oct. 2007. U.S. National Library of Medicine. 3 Dec. 2007 .

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[1] The American Heritage® Dictionary of the English Language, Fourth Edition

Copyright © 2006 by Houghton Mifflin Company.

[2] Blundell, J.E. Trends in Pharmacological Sciences. 1991, 12, 147-157

[3] Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999). "Ghrelin is a growth-hormone-releasing acylated peptide from stomach". Nature 402 (6762): 656-60.

[4] Bray, G.A.; Blackburn, G.L.; Ferguson, J.M.; Greenway, F.L.; Jain, A.K.; Mendel, C.M.; Ryan, D.H.; Schwartz, S.L.; Scheinbaum, M.L.; Seaton, T.B. Obesity Res. 1999, 7, 189-198.

[5] Finer, N.; Bloom, S.R.; Frost, G.S.; Banks, L.M.; Griffiths, J. Diab. Obes. Met.,2000,2,105-112

Fujioka, K.; Seatin, T.B.; Rowe, E.; Jelinek, C.A.; Raskin, P.; Lebovitz, H.E.; Weinstein, S.P. Diab. Obes. Met., 2000,2, 175-187.

[6] Blundell, J.E. Int. J. Obesity, 1977, 1, 15-42.

[7] Goldstein, D.J.; Rampey Jr., A.H.; Enas, G.G.; et al. Fluoxetine: a randomized clinical trial in the treatment of obesity. Int. j obes. Relat. Metab. Disord. 1994, 18 (3),129-135.

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