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) Mc4r gene expression in DMH of control (AAV-GFP injected MC4R floxed) and DMH-MC4RKO (AAV-Cre injected Mc4r floxed) mice assessed by in situ hybridization (upper panels, dark field showing Mc4r expression; lower panels, H&E staining with DMH outlined). (B) Body weight curves (n = 12–14/group), (C) body composition (n = 7–8/group), and (D) body length (n = 10/group) in DMH-MC4RKO and control mice. (E and F) (E) REE and TEE and (F) total and ambulatory activity levels in DMH-MC4RKO and control mice at 22°C and 30°C (n = 7–8/group). (G and H) (G) Food intake and (H) body weight at the time of food intake measurement (n = 9/group). (I and J) (I) Acute energy expenditure (n = 5–6/group) and (J) food intake (n = 4/group) responses to MTII as compared with vehicle. (K) Cold tolerance test (n = 4–6/group). (L) Histology of BAT, epididymal WAT, and inguinal WAT from DMH-MC4RKO and control mice (H&E staining). Scale bar: 100 μm. All experiments were performed 2 to 2.5 months after viral injection. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01 vs. controls by Student’s t test.