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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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-express-ing 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.

Original languageEnglish (US)
Pages (from-to)10993-11005
Number of pages13
JournalJournal of Biological Chemistry
Issue number28
StatePublished - Jul 13 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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