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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
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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.
1
The American Heritage® Dictionary of the English Language, Fourth Edition
Copyright © 2006 by Houghton Mifflin Company.
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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.
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.
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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.).
2
Blundell, J.E. Trends in Pharmacological Sciences. 1991, 12, 147-157
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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 Kojima3, 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.
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.
3
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©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.
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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.
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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
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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
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.
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©Blundell, J. E., & Halford, G. (1998). Serotonin and appetite regulation: Implications
for the pharmacological treatment of obesity. CNS Drugs, 9(6), 473-495.
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“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).
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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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.
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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), 9871002.
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
<http://www.nlm.nih.gov/medlineplus/obesity.html>.