Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations

Min Chen, Yogendra B. Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui (Herb) Sun, Thuy Ho, Eric A. Wilson, Yong Qi Li, Oksana Gavrilova, Lee S. Weinstein

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Gsα, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous Gsα- 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 Gsα imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting Gsα 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 Gsα. Our results show that Gsα imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from Gsα mutations and that DMH MC4R/Gsα signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold.

Original languageEnglish (US)
Pages (from-to)500-510
Number of pages11
JournalJournal of Clinical Investigation
Volume127
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

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Mediodorsal Thalamic Nucleus
Hypothalamus
Obesity
Mutation
Brown Adipose Tissue
Alleles
Mothers
Energy Metabolism
Melanocortin Receptors
Hyperphagia
Neurotransmitter Receptor
Gene Deletion
Hormones
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations. / Chen, Min; Shrestha, Yogendra B.; Podyma, Brandon; Cui, Zhenzhong; Naglieri, Benedetta; Sun, Hui (Herb); Ho, Thuy; Wilson, Eric A.; Li, Yong Qi; Gavrilova, Oksana; Weinstein, Lee S.

In: Journal of Clinical Investigation, Vol. 127, No. 2, 01.02.2017, p. 500-510.

Research output: Contribution to journalArticle

Chen, M, Shrestha, YB, Podyma, B, Cui, Z, Naglieri, B, Sun, HH, Ho, T, Wilson, EA, Li, YQ, Gavrilova, O & Weinstein, LS 2017, 'Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations', Journal of Clinical Investigation, vol. 127, no. 2, pp. 500-510. https://doi.org/10.1172/JCI88622
Chen, Min ; Shrestha, Yogendra B. ; Podyma, Brandon ; Cui, Zhenzhong ; Naglieri, Benedetta ; Sun, Hui (Herb) ; Ho, Thuy ; Wilson, Eric A. ; Li, Yong Qi ; Gavrilova, Oksana ; Weinstein, Lee S. / Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 2. pp. 500-510.
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