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

• 成果类型: Article
• 署名作者: Xun, Yu; Jiang, Yiao; Xu, Baijie; Tang, Miao; Ludwig, Sara; Nakamura, Kazuhiro; Mukhopadhyay, Saikat; Liu, Chen; Beutler, Bruce; Zhang, Zhao
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Nagoya University; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12377
• DOI: 10.1126/science.adp3989
• 发表日期: 2025-06-05
• 关键词: protein-coupled receptors; gene; obesity; disruption; localization; mutations; pathways; adcy3; mouse; mc4r

摘要

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 G alpha 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.