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

Brandon Podyma, Hui Sun, Eric A Wilson, Bradley Carlson, Ethan Pritikin, Oksana Gavrilova, Lee S Weinstein, Min Chen

The Journal of biological chemistry 2018 Jul 13

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

Citation

Brandon Podyma, Hui Sun, Eric A Wilson, Bradley Carlson, Ethan Pritikin, Oksana Gavrilova, Lee S Weinstein, Min Chen. The stimulatory G protein Gsα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism. The Journal of biological chemistry. 2018 Jul 13;293(28):10993-11005