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
(A) Food intake (left) and body weight (right) of mDMHGsKO and control mice (n = 4–5/group). (B) Food intake (left) and body weight (right) of pDMHGsKO and control mice (n = 4/group). Food intake was measured at 2 months after viral injection and is normalized to body weight. (C) Absolute food intake (kcal/d, left) and body weight (right) of young mDMHGsKO and control mice at 2 weeks after injection (n = 7–10/group). (D and E) Food intake response to MC4R agonist MTII (expressed as percentage of intake vs. intake after vehicle injection) in (D) mDMHGsKO mice (n = 7–10/group) and (E) pDMHGsKO mice (n = 4/group) and their respective controls. (F and G) REE and TEE at 22°C and 30°C in (F) mDMHGsKO mice and (G) pDMHGsKO mice and their respective controls at 2 to 2.5 months after viral injection (n = 7–12/group). (H and I) Total and ambulatory (Amb) activity levels in (H) mDMHGsKO mice and (I) pDMHGsKO mice and their respective controls (n = 7–12/group). (J and K) Increase in energy expenditure in response to MTII in (J) mDMHGsKO mice (n = 6–10/group) and (K) pDMHGsKO (n = 6) and their respective controls. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01 vs. controls by Student’s t test.