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Gs? deficiency in the dorsomedial hypothalamus underlies obesity associated with Gs? mutations.

ABSTRACT: Gs?, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gs?-inactivating mutations lead to obesity in Albright hereditary osteodystrophy (AHO) patients, but only when the mutations occur on the maternal allele. This parent-of-origin effect is due to Gs? imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gs? expression on the maternal allele, but not the paternal allele, in the dorsomedial nucleus of the hypothalamus (DMH) developed obesity and reduced energy expenditure without hyperphagia. Although maternal Gnas deletion impaired activation of brown adipose tissue (BAT) in mice, their responses to cold environment remained intact. Similar findings were observed in mice with DMH-specific deficiency of melanocortin MC4R receptors, which are known to activate Gs?. Our results show that Gs? imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from Gs? mutations and that DMH MC4R/Gs? signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold.

PROVIDER: S-EPMC5272175 | BioStudies |

REPOSITORIES: biostudies

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