Neuropharmacology of Obesity:
My Receptors Made Me Eat It

Stephen M. Stahl, M.D., Ph.D.

Issue: Specific neurotransmitter and hormone receptors regulate appetite, eating behavior, and weight gain.

5-HT_2C Receptors

For many years, pharmacologists have known that increasing the availability of serotonin (5-HT) in the synaptic cleft or direct activation of some 5-HT receptors reduces food consumption, while decreasing 5-HT receptor activation brings about the opposite effect.¹ Recent research more specifically implicates the 5-HT_2C receptor subtype as playing the key role in regulating appetite.^1,2 For example, mutant mice that lack the 5-HT_2C receptor are obese. Activating 5-HT_2C receptors decreases eating behavior in rats.

A 5-HT_2C mechanism may also underlie weight reduction in humans taking appetite suppressants. Specifically, fenfluramine (now withdrawn from marketing) releases serotonin to act at all 5-HT receptors, but it may be the action of serotonin specifically at the 5-HT_2C subtype that is important, since fenfluramine and its metabolite norfenfluramine may also be agonists at the 5-HT_2C receptor.¹

Serotonin reuptake inhibitors, including both selective serotonin reuptake inhibitors (SSRIs) and dual 5-HT plus norepinephrine reuptake inhibitors (SNRIs), can also reduce appetite, at least acutely.^3,4 Fluoxetine, arguably the most anorexigenic of the SSRIs, and with a specific indication for bulimia, is also the only SSRI with direct 5-HT_2C agonist activity in addition to its 5-HT reuptake blocking properties.⁵ The most recently marketed appetite suppressant is sibutramine (Meridia); its mechanism works by both 5-HT and norepinephrine reuptake blockade,⁴ much like higher doses of venlafaxine. The dual proserotonergic and pronoradrenergic actions of sibutramine may have a net pharmacologic effect similar to fen/phen, namely, 5-HT release by fenfluramine and norepinephrine/dopamine release by phentermine.⁴ Proadrenergic actions thus seem to synergize with proserotonergic actions at 5-HT_2C receptors. This may be either by a central mechanism that reduces food intake or by a peripheral mechanism that increases thermogenesis via stimulation of beta₃-adrenergic receptors in adipose tissue.⁴

Beta₃-Adrenergic Receptors

The 3 distinct subtypes of beta receptors⁶ are the beta₁ receptor, which is predominantly a cardiac receptor and the target for beta blockers; beta₂ receptor, which is in the lungs (the target of bronchodilating beta agonists) and also found in uterus and skeletal muscle; and beta₃ receptor, expressed primarily in adipose tissue, where it regulates energy metabolism and thermogenesis (turning fat into heat and energy), especially in response to norepinephrine.^6,7

Evidence that the beta₃-adrenergic receptors play an active role in weight control in humans comes from the finding that a genetic variant of this receptor constitutes a susceptibility factor for the onset of morbid obesity as well as non-insulin-dependent diabetes.⁷ Specifically, this variant of the beta₃ receptor is associated with hereditary obesity in Pima Indians from Arizona and demonstrated an increased incidence in obese patients in Japan. It also exists in nonobese individuals, including a fourth of African Americans and about 10% of the general population in Europe and the United States.⁷

These various findings suggest a strategy for treating obesity by stimulating metabolism and peripheral burning of fat, rather than by acting on central satiety. The proadrenergic agent sibutramine increases norepinephrine peripherally at the beta₃-adrenergic receptors in adipose tissue,⁴ thus stimulating thermogenesis and increasing oxygen consumption, leading to weight loss.

Histamine-1 Receptors

The exact neurotransmitter role of histamine in the CNS still remains an enigma. However, regulation of arousal and appetite by histamine has long been suggested by observations that H₁ antagonists are not only sedating but also increase appetite and weight in experimental animals and humans.⁸ Binding studies of antidepressants and antipsychotics suggest that sedation and weight gain in humans are proportional to their ability to block these H₁ receptors.⁸

Neuropeptide Receptors and the Leptin Story

At least 3 peptides are implicated in the regulation of food intake, energy expenditure, and whole body energy balance in both rodents and humans, and are found both peripherally as hormones and centrally. These are galanin, neuropeptide Y, and leptin.^9-12 The physiologic roles of these peptides in regulating body weight via their CNS receptors remain somewhat obscure, although the effects of leptin on food intake and energy expenditure are thought to be mediated centrally via neuropeptide Y.^9-12

The role of peripheral leptin has been more extensively investigated.^8-11 Leptin, a member of the interleukin 6 cytokine family, is a peptide found in multiple tissues and secreted by white adipose cells, where it is highly correlated with body fat mass and size of fat cells. The peripheral effects of leptin include regulation of insulin secretion, and energy metabolism in fat cells and skeletal muscle, where it seems to play a role in ensuring the maintenance of adequate energy stores and thereby protects against starvation. It also acts as a metabolic signal that regulates how nutritional status affects reproductive function. Cortisol and insulin are potent stimulators of leptin, whereas beta-adrenergic agonists reduce leptin expression.

Administration of leptin to genetically obese mice reduces their food intake and makes them lose weight.^9-12 Congenital leptin deficiency in humans is associated with severe early-onset obesity. Somewhat paradoxically, however, plasma leptin levels are increased in obese women and decreased in women with anorexia nervosa.¹³ Plasma neuropeptide Y and galanin levels are also increased in obese women. Since leptin levels are chronically increased in obese humans, this suggests that obesity may be associated with malfunctioning leptin receptors, a condition called leptin resistance, since leptin is unable to generate an adequate response when its receptor is occupied. Improving responsivity to leptin in obese patients may be one key to weight loss.

Understanding the neuropharmacology of weight gain will hopefully lead to better management of obesity.

REFERENCES

1. Curzon G, Gibson EL, Oluyomi AO. Appetite suppression by commonly used drugs depends on 5HT receptors but not on 5HT availability. Trends Pharmacol Sci 1998;13:21-25

2. Baxter G, Kennett G, Blaney G, et al. 5HT2 receptor subtypes: a family re-united? Trends Pharmacol Sci 1995;16:105-110

3. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. In press

4. Sibutramine for obesity. Med Lett Drugs Ther 1998;40:32

5. Stahl SM. Not so selective serotonin reuptake inhibitors J Clin Psychiatry 1998;59.343-344

6. Strosberg AD, Pietri-Rouxel F. Function and regulation of the beta₃-adrenoceptor. Trends Pharmacol Sci 1996;17:373-381

7. Strosberg AD. Association of beta₃-adrenoceptor polymorphism with obesity and diabetes: current status. Trends Pharmacol Sci 1997;18: 449-455

8. Stahl SH Essential Psychopharmacology. New York, NY: Cambridge University Press; 1996

9. Houseknecht KL, Baile CA, Matteri RL, et al. The biology of leptin: a review. J Anim Sci 1998;76:405-420

10. Canpfield LA, Smith FJ, Burn P. Strategies and potential molecular targets for obesity treatment. Science 1998;290 1383-1387

11. Flier JS, Maratos-Flier E. Obesity and the hypothalamus: novel peptides for new pathways. Cell 1998;92:437-440

12. Jackson RS, Creemers JW, Ohagi S, et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 1997;16:303-306

13. Baranowska B, Wasilewska-Dzinbianska E, Radzidowsda M, et al. Galanin and leptin release in obese women and in women with anorexia nervosa. Metabolism 1997;46:1284-1289

Brainstorms aims to provide updates of novel concepts emerging from the neurosciences that have relevance to practitioners.

From the Clinical Neuroscience Research Center in San Diego and the Department of Psychiatry at the University of California San Diego.