Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations
Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations
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DOI：
10.1172/jci88622
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发表时间：
2017-02-01
影响因子：
15.9
通讯作者：
Weinstein, Lee S.
中科院分区：
文献类型：
--
作者：
Chen, Min;Shrestha, Yogendra B.;Weinstein, Lee S.
由Gnas编码的G(s) α介导激素和神经递质受体刺激的cAMP生成。杂合G(s) α失活突变导致奥尔布赖特遗传性骨营养不良（who）患者肥胖，但仅当突变发生在母体等位基因上时。这种亲本效应是由于中枢神经系统中的G(s) α印记，尽管相关的中枢神经系统区域尚不清楚。我们现在已经证明，在下丘脑背内侧核（DMH）中，Gnas基因缺失会破坏母系等位基因上G(s) α的表达，但不会破坏父系等位基因上的G(s) α表达，小鼠会出现肥胖，减少能量消耗，但不会出现贪食。虽然母系Gnas缺失损害了小鼠棕色脂肪组织（BAT）的激活，但小鼠对寒冷环境的反应保持不变。在dmh特异性缺乏黑素皮质素MC4R受体的小鼠中也观察到类似的结果，已知该受体可激活G(s) α。我们的研究结果表明，DMH中的G(s) α印记是由G(s) α突变导致的亲本起源代谢表型的基础，DMH MC4R/G(s) α信号传导对能量消耗和BAT激活的调节很重要，但对寒冷的代谢反应不起作用。
G(s)alpha, encoded by Gnas, mediates hormone and neurotransmitter receptor-stimulated cAMP generation. Heterozygous G(s)alpha-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 G(s)alpha imprinting in the CNS, although the relevant CNS regions are unknown. We have now shown that mice with a Gnas gene deletion disrupting G(s)alpha 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 G(s)alpha. Our results show that G(s)alpha imprinting in the DMH underlies the parent-of-origin metabolic phenotype that results from G(s)alpha mutations and that DMH MC4R/G(s)alpha signaling is important for regulation of energy expenditure and BAT activation, but not the metabolic response to cold.