The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted.

Significance: Physiological concentrations of hydrogen sulfide (H ₂ S) exert potent prosurvival actions. We demonstrate that the cytoprotective actions of H ₂ S are mediated in part via a second gaseous signaling molecule, nitric oxide (NO). We found that cystathionine γ-lyase (CSE) KO mice with reduced H ₂ S levels exhibit increased oxidative stress and an exacerbated response to myocardial ischemia/reperfusion injury. CSE KO mice also exhibit reduced levels of NO and reduced NO synthesis via endothelial NO synthase (eNOS). Both oxidative stress and myocardial injury in CSE KO mice were attenuated by exogenous H ₂ S therapy, with increased eNOS function and restoration of NO levels. These findings provide insight into H ₂ S-mediated cytoprotetion and important information regarding the translation of H ₂ S therapy to the clinic.

The melanocortin-4 receptor (MC4R) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of alpha-MSH to the MC4R leads to increased cAMP production. Recent pharmacological and genetic studies have provided compelling evidence that MC4R is an important regulator of food intake and energy homeostasis. Allelic variants of MC4R were reported in some children with early-onset severe obesity. However, few studies have been performed to confirm that these allelic variants result in an impairment of the receptor's function. In this study, we expressed wild-type and variant MC4Rs in HEK293 cells and systematically studied ligand binding, agonist-stimulated cAMP, and cell surface expression. Six of the 11 mutants examined had either decreased (S58C, N62S, Y157S, C271Y) or no (P78L, G98R) ligand binding, with proportional impairments in [Nle4, d-Phe7]-alpha-MSH-stimulated cAMP production. Confocal microscopy confirmed that the observed decreases in hormone binding by these mutants are associated with decreased cell surface expression due to intracellular retention of the mutants. The other five allelic variants (D37V, P48S, V50M, I170V, N274S) were found to be expressed at the cell surface and to bind agonist and respond with increased cAMP production normally. The data on these latter five variants raise the question as to whether they are indeed causative of the obesity or not and, if so, by what mechanism. Our data, therefore, stress the importance of characterizing the properties of MC4R variants associated with early-onset severe obesity. We further propose a classification scheme for mutant MC4Rs based upon their properties.