Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

• 成果类型: Article
• 署名作者: Lin, Hui; Ma, Chuanshun; Cai, Kui; Guo, Lulu; Wang, Xuemei; Lv, Lin; Zhang, Chao; Lin, Jun; Zhang, Daolai; Ye, Chuan; Wang, Tengwei; Huang, Shenming; Han, Jifei; Zhang, Zihao; Gao, Junyan; Zhang, Mingxiang; Pu, Zhao; Li, Fengyang; Guo, Yongyuan; Zhou, Xiaojun; Qin, Chengxue; Yi, Fan; Yu, Xiao; Kong, Wei; Jiang, Changtao; Sun, Jin-Peng
• 署名单位: Shandong University; Shandong University; Peking University; Shandong University; Shandong University; Shandong University; Shandong University; Shandong University; Binzhou Medical University; University of Toronto; Shandong University; Shandong University; Shandong University; Peking University; Peking University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8093
• DOI: 10.1126/science.ado4188
• 发表日期: 2025-05-01
• 关键词: beta-arrestin recruitment; inducible factor 2-alpha; g-protein; weight-gain; activation; microbiota; peptides; bacteria; gromacs

摘要

Ceramides play a central role in human health and disease, yet their role as systemic signaling molecules remain poorly understood. In this work, we identify formyl peptide receptor 2 (FPR2) as a membrane receptor that specifically binds long-chain ceramides (C14 to C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis through Gi cyclic adenosine monophosphate signaling pathways, an effect that is reversed in the absence of FPR2. We present three cryo-electron microscopy structures of FPR2 in complex with Gi trimers bound to C16:0, C18:0, and C20:0 ceramides. The hydrophobic tails are deeply embedded in the orthosteric ligand pocket, which has a limited amount of plasticity. Modification of the ceramide binding motif in closely related receptors, such as FPR1 or FPR3, converts them from inactive to active ceramide receptors. Our findings provide a structural basis for adipocyte thermogenesis mediated by FPR2.