Address correspondence to: Judith Korner, Columbia University College of Physicians and Surgeons, 630 West 168th Street, Black Building, Room 905, New York, New York 10032, USA. Phone:(212) 305-3725; Fax:(212) 305-2282; E-mail: jk181@ columbia. edu. Conflict of interest: Louis J. Aronne acts as a consultant, speaker, or advisor or receives research support from the following: Abbott Laboratories, Amgen, Bristol-Myers Squibb Company, Ortho-McNeil Pharmaceuticals, Otsuka Pharmaceuticals, Regeneron Pharmaceuticals, Roche Pharmaceuticals, Sanofi-Synthelabo Inc., and TAP Pharmaceutical Products Inc. Nonstandard abbreviations used: diabetes mellitus (DM); janus kinase–signal transducers and activators of transcription (JAK-STAT); neuropeptide Y (NPY); melanin-concentrating hormone (MCH); glucagon-like peptide-1 (GLP-1); α-melanocytestimulating hormone (α-MSH); proopiomelanocortin (POMC); agouti-related protein (AGRP); peptide YY3–36 (PYY); Food and Drug Administration (FDA). through the janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway. The etiology of central leptin resistance may involve a suppressor of the cytokine-signaling family SOCS-3, which is induced by leptin and prevents activation of the JAK-STAT pathway (1). From an evolutionary perspective, the physiological function of leptin is probably as a metabolic switch that serves to preserve body fat during times of famine, rather than an antiobesity agent that suppresses body fat during times of food excess (2). Leptin is known to affect the gene expression and synthetic pathway of both anorectic (appetite-suppressing) and orexigenic (appetite-stimulating) substances (Figure 1). Neuropeptide Y (NPY) is a hypothalamic orexigenic peptide produced in the arcuate nucleus, which increases food intake and decreases energy expenditure. The expression of NPY mRNA is inhibited by leptin. In the lateral hypothalamus, melanin-concentrating hormone (MCH), an orexigenic peptide, is increased with fasting and leptin deficiency. Disruption of the MCH gene or administration of an MCH1 receptor antagonist results in hypophagia and leanness in rodents (3, 4). Glucagon-like peptide–1 (GLP-1) and neurotensin are peptides that inhibit the ability of MCH to induce eating. Leptin also downregulates endocannabinoids that act as cannabinoid receptors in the hypothalamus and stimulate food intake (5). Conversely, leptin stimulates the expression of genes encoding anorexigenic peptides. α-Melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), and cocaine-and amphetamine-regulated transcript are hypothalamic peptides expressed in the same subset of neurons within the arcuate nucleus of the hypothalamus. These peptides are positively regulated by leptin and produce anorexia.

The melanocortin system is under intensive investigation because of evidence in both rodents and humans of its control of energy homeostasis (6). There are five different receptors for α-MSH, two of which (MC3R and MC4R) are primarily expressed in the brain. The highest MC3R expression level is in the hypothalamus and limbic system, whereas MC4R