Molecular Determinants of Energy Homeostasis

Abstract

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessMolecular Determinants of Energy HomeostasisJoel Elmquist D.V.M., PH.D.Jeffrey Zigman M.D., PH.D.Michael Lutter M.D., PH.D.,Joel Elmquist D.V.M., PH.D.Search for more papers by this authorJeffrey Zigman M.D., PH.D.Search for more papers by this authorMichael Lutter M.D., PH.D.Search for more papers by this author,Published Online:1 Jul 2006AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail The control of body weight and energy homeostasis in humans has received much attention in recent years because of the rising rates of obesity. The field of psychiatry has become interested in these processes, since many of our medications perturb neurotransmitter systems regulating feeding mechanisms and result in weight gain and often diabetes. In the past decade, the understanding of the brain sites controlling body weight and glucose homeostasis has increased dramatically. One key site is the arcuate nucleus of the hypothalamus because it integrates peripheral signals of energy balance (shown in diagram). For example, leptin (from the Greek leptos , meaning thin) is a circulating hormone produced by white adipose tissue that regulates feeding behavior. Exogenous leptin reduces appetite and feeding; leptin deficiency (both mice and humans with mutations in the leptin gene) causes extreme obesity. Leptin directly activates proopiomelanocortin (POMC) cells in the arcuate nucleus (shown on the right) to increase the release of melanocortin peptides, including the POMC product α-melanocyte stimulating hormone (α-MSH). Melanocortins (MC) inhibit food intake and regulate metabolism, energy storage, insulin secretion, and gastrointestinal motility predominantly via projections to MC 4 receptor neurons. Moreover, leptin also directly inhibits arcuate neurons, which produce agouti-related protein and neuropeptide Y. Agouti-related protein is an endogenous antagonist of α-MSH at MC 4 receptors. Another key metabolic signal that acts directly on the melanocortin circuit in the arcuate nucleus is the hormone ghrelin. During periods of reduced calorie availability, the stomach also increases the release of ghrelin before meals. Elevated ghrelin in the presence of low leptin levels induces appetite and results in obesity (e.g., ghrelin levels are high in Prader-Willi syndrome). Activation of ghrelin receptors in the arcuate nucleus is thought to activate neuropeptide Y and agouti-related protein neurons to promote weight gain. Of particular interest to psychiatrists is that serotonergic neurons innervate the hypothalamus, including POMC, neuropeptide Y, and agouti-related protein neurons. One key serotonin (5-HT) receptor that regulates body weight is the 5-HT 2C receptor. These receptors, expressed by POMC neurons in the arcuate, are required for the anorectic effect of d -fenfluramine. Thus, antagonism of 5-HT 2C receptors by second-generation antipsychotics represents a potential mechanism for the weight gain and dysregulation of glucose homeostasis associated with these agents. Figure 1. In the micrograph on the right, the white arrows show leptin activation of POMC neurons in the arcuate nucleus of the hypothalamus (black silver grains denoting POMC mRNA). The brown cytoplasmic label in the nucleus is Fos-like immunoreactivity. Fos is a widely used marker of neuronal activity. Adapted from Elmquist JK, Marcus JN: Rethinking the central causes of diabetes. Nat Med 2003; 9:645–647.Dallas, TexasAddress reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NE5.110, Dallas, TX 75390-9070; [email protected] (e-mail). FiguresReferencesCited byDetailsCited ByNeuroendocrine Control of Energy StoresMolecular Endocrinology, Vol. 26, No. 12PLoS ONE, Vol. 6, No. 4Journal of Central Nervous System Disease, Vol. 3Psychiatric Quarterly, Vol. 81, No. 3Postgraduate Medicine, Vol. 122, No. 4 Volume 163Issue 7 July, 2006Pages 1137-1137THE AMERICAN JOURNAL OF PSYCHIATRY July 2006 Volume 163 Number 7 Metrics PDF download History Published online 1 July 2006 Published in print 1 July 2006