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 and B) Results of glucose tolerance tests (glucose curve, left; AUC, right) performed on (A) mDMHGsKO mice (n = 7–9/group) and (B) pDMHGsKO mice (n = 5–7/group) and their respective controls. (C and D) Results of insulin tolerance tests (glucose curves as percentage of baseline, left; area below baseline [ABB], right) performed in (C) mDMHGsKO mice (n = 7–10/group) and (D) pDMHGsKO mice (n = 4–6/group) and their respective controls. Experiments in parts A–D were performed in mice at 2.5 to 3 months after injection. (E) Glucose tolerance test (glucose curve, left; AUC, right) performed on mDMHGsKO and control mice at 2 weeks after injection (n = 4–6/group). (F) Body weight of mice at the time of glucose tolerance tests shown in part E. (G) Fasting blood glucose levels in mDMHGsKO and control mice at 2 weeks after viral injection. (H) Serum insulin levels at time 0 and 120 minutes during glucose tolerance tests shown in part E. Data are shown as mean ± SEM. *P < 0.05 vs. controls by Student’s t test.