Xun Yu, Jiang Yiao, Xu Baijie, Tang Miao, Ludwig Sara, Nakamura Kazuhiro, Mukhopadhyay Saikat, Liu Chen, Beutler Bruce, Zhang Zhao
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Science. 2025 Jun 5;388(6751):eadp3989. doi: 10.1126/science.adp3989.
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 and 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 that lead to obesity through hyperphagia. GPR45 was expressed in paraventricular nucleus of the hypothalamus (PVH), where it localized to cilia and recruited Gα 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.
黑皮质素系统在中枢调节能量平衡，其关键成分如黑皮质素-4受体（MC4R）和腺苷酸环化酶3（ADCY3）存在于神经元初级纤毛中。MC4R和ADCY3的突变以及纤毛功能障碍会导致肥胖，但黑皮质素信号在纤毛中如何发挥作用仍不清楚。利用小鼠随机种系诱变，我们在GPR45中鉴定出两个错义突变，这些突变通过食欲过盛导致肥胖。GPR45在下丘脑室旁核（PVH）中表达，定位于纤毛，并募集Gα通过ADCY3增加纤毛环磷酸腺苷（cAMP）。GPR45与PVH纤毛中的MC4R共定位，并促进纤毛MC4R的激活。PVH或MC4R神经元中GPR45的缺失导致肥胖。这些发现确立了GPR45作为纤毛黑皮质素系统的关键调节因子，连接MC4R和ADCY3。
