Melanocortin receptors and energy homeostasis

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Abstract
Purpose of review This article highlights new information regarding the physiology of the central melanocortin system and how defects in it contribute to human metabolic disease. Recent findings Selective abolition of leptin action on pro-opiomelanocortin neurons causes an obese phenotype, demonstrating that leptin signaling through pro-opiomelanocortin neurons is essential for normal energy homeostasis. Novel roles of leptin are also becoming apparent with evidence that acetylation of α-melanocyte-stimulating hormone into its more biologically activity form is leptin dependent. Leptin can also regulate hepatic glucose fluxes through a central melanocortin-dependent pathway. We review evidence that the brain stem melanocortin system mediates the effects of cholecystokinin, suggesting that the melanocortin system integrates short-term satiety signals as well as long-term adipostatic signals like leptin. The downstream targets of MC4-R are now becoming apparent with melanin-concentrating hormone and brain-derived neurotrophic factor implicated as key ‘second order’ mediators. Evidence from different ethnic groups shows MC4-R mutations to be the most common single gene disorder causing obesity. The functional properties of naturally occurring human mutants suggest the N-terminal domain of the MC4-R may function as a tethered intramolecular ligand, maintaining constitutive receptor activity. Summary Recent studies have reiterated the critical role the central melanocortin pathway plays in the control of energy balance. Given the public health challenge that obesity presents, the potential attractiveness of the melanocortin system as a therapeutic target only grows as knowledge of its molecular physiology increases.