GPR45调节室旁下丘脑初级纤毛上的Gαs，控制食物摄入

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-06-05 DOI:10.1126/science.adp3989

Yu Xun, Yiao Jiang, Baijie Xu, Miao Tang, Sara Ludwig, Kazuhiro Nakamura, Saikat Mukhopadhyay, Chen Liu, Bruce Beutler, Zhao Zhang

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引用次数: 0

摘要

黑素皮质素系统集中调节能量稳态，关键成分如黑素皮质素-4受体（MC4R）和腺苷酸环化酶3 （ADCY3）在神经元初级纤毛。MC4R和ADCY3的突变以及纤毛功能障碍导致肥胖，但黑素皮质素信号如何在纤毛中起作用尚不清楚。通过小鼠随机种系诱变，我们发现了G蛋白偶联受体45 （Gpr45）的两个错义突变，这些突变通过嗜食导致肥胖。GPR45表达于下丘脑室旁核（PVH），定位于纤毛，通过ADCY3募集Gαs增加纤毛环磷酸腺苷（cAMP）。GPR45在PVH纤毛中与MC4R共定位，促进纤毛MC4R的激活。PVH或MC4R+神经元中GPR45的缺失导致肥胖。这些发现表明GPR45是纤毛黑素皮质素系统的关键调节因子，连接MC4R和ADCY3。

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GPR45 modulates Gαs at primary cilia of the paraventricular hypothalamus to control food intake

The melanocortin system centrally regulates energy homeostasis, with key components such as melanocortin-4 receptor (MC4R) and adenylyl cyclase 3 (ADCY3) in neuronal primary cilia. Mutations in MC4R and ADCY3 as well as ciliary dysfunction lead to obesity, but how melanocortin signaling works in cilia remains unclear. Using mouse random germline mutagenesis, we identified two missense mutations in G protein–coupled receptor 45 (Gpr45) that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gα_s to increase ciliary cyclic adenosine monophosphate (cAMP) via ADCY3. GPR45 colocalized with MC4R in PVH cilia and promoted ciliary MC4R activation. Loss of GPR45 in the PVH or MC4R⁺ neurons caused obesity. These findings establish GPR45 as a key regulator of the ciliary melanocortin system, bridging MC4R and ADCY3.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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