The stimulatory G protein Gsα is required in melanocortin 4 receptor–expressing cells for normal energy balance, thermogenesis, and glucose metabolism

Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein G(s), but whether G(s) mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous G(s)-inactivating mutations, only develop obesity when the G(s) mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates G(s) imprinting within the central nervous system (CNS) in this disorder. In this study, we examined the effects of G(s) in MC4R-expressing cells on metabolic regulation. Mice with homozygous G(s) deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological response mediated by MC4R-G(s) signaling, even though baseline PYY levels were elevated in these mice. In G(s) heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a G(s) deletion on the maternal allele in MC4R-expressing cells, whereas food intake was unaffected. These results demonstrate that G(s) signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that G(s) imprinting in MC4R-expressing cells contributes to obesity in G(s) knockout mice and probably in individuals with Albright hereditary osteodystrophy as well.