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.
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) Gsα mRNA levels in the DMH (indicated with dashed outline) of WT mice and mice with germline heterozygous Gnas deletion on either the maternal (E1m–) or paternal (E1p–) allele (upper panel: dark field showing Gsα expression; lower panel: H&E staining). Original magnification: ×20. (B) Quantification of in situ hybridization study with Gsα mRNA levels expressed as percentage of WT. n = 5–8/group. *P < 0.05, E1m– vs. WT; #P < 0.05, E1m– vs. E1p–. (C and D) Body weight curves of (C) male mDMHGsKO and (D) pDMHGsKO mice and their control littermates. (E and F) Body composition of (E) mDMHGsKO and (F) pDMHGsKO mice and their control littermates at 2 to 2.5 months after AAV injection (n = 5–10/group). (*P < 0.05 or **P < 0.01 vs. controls by Student’s t test.) (G) Body length of mDMHGsKO (left) and pDMHGsKO (right) mice and their respective controls at 4 to 5 months after injection (n = 5–14/group). (H) Histology of BAT, epididymal WAT (Epi), and inguinal WAT (Ing) from mDMHGsKO and pDMHGsKO mice and their respective controls (H&E staining). Scale bar: 100 μm. Data are shown as mean ± SEM.