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

ABSTRACT: Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein G_sα, but whether G_sα mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous G_sα-inactivating mutations, only develop obesity when the G_sα mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates G_sα imprinting within the central nervous system (CNS) in this disorder. In this study, we examined the effects of G_sα in MC4R-expressing cells on metabolic regulation. Mice with homozygous G_sα 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_sα signaling, even though baseline PYY levels were elevated in these mice. In G_sα heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a G_sα deletion on the maternal allele in MC4R-expressing cells, whereas food intake was unaffected. These results demonstrate that G_sα signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that G_sα imprinting in MC4R-expressing cells contributes to obesity in G_sα knockout mice and probably in individuals with Albright hereditary osteodystrophy as well.

SUBMITTER: Podyma B 

PROVIDER: S-EPMC6052205 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature