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

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

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.

Authors

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

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Figure 4

Cold tolerance and cardiovascular function in mDMHGsKO and pDMHGsKO mice.

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Cold tolerance and cardiovascular function in mDMHGsKO and pDMHGsKO mice...
(A and B) Relative BAT gene expression in (A) mDMHGsKO mice and (B) pDMHGsKO mice and their respective controls (n = 5–6/group). (C) Rectal temperature before (0 hours) and after exposure to 4°C for 6 hours (left panel, mDMHGsKO and control mice [n = 9–13/group]; right panel, pDMHGsKO and control mice [n = 4–6/group]). (D and E) BAT Ucp1 gene expression at room temperature (RT) and after 6 hours at 4°C (cold) in (D) mDMHGsKO mice and (E) pDMHGsKO mice and their respective controls (n = 5–10/group). #P < 0.05 vs. room temperature; *P < 0.05 vs. controls. (F) Heart rate and (G) blood pressure in mDMHGsKO mice and pDMHGsKO mice and their respective controls (n = 6–7/group). Data are shown as mean ± SEM. *P < 0.05 vs. controls by Student’s t test (with correction for repeated measures for parts A and B).