| First Author | Podyma B | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 28 | Pages | 10993-11005 |
| PubMed ID | 29794140 | Mgi Jnum | J:267133 |
| Mgi Id | MGI:6197424 | Doi | 10.1074/jbc.RA118.003450 |
| Citation | Podyma B, et al. (2018) The stimulatory G protein Gsalpha is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism. J Biol Chem 293(28):10993-11005 |
| abstractText | Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein Gsalpha, but whether Gsalpha mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous Gsalpha-inactivating mutations, only develop obesity when the Gsalpha mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates Gsalpha imprinting within the central nervous system (CNS) in this disorder. In this study, we examined the effects of Gsalpha in MC4R-expressing cells on metabolic regulation. Mice with homozygous Gsalpha 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-Gsalpha signaling, even though baseline PYY levels were elevated in these mice. In Gsalpha heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a Gsalpha deletion on the maternal allele in MC4R-expressing cells, whereas food intake was unaffected. These results demonstrate that Gsalpha signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that Gsalpha imprinting in MC4R-expressing cells contributes to obesity in Gsalpha knockout mice and probably in individuals with Albright hereditary osteodystrophy as well. |
