Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

作者：Hui Lin, Chuanshun Ma, Kui Cai, Lulu Guo, Xuemei Wang, Lin Lv, Chao Zhang, Jun Lin, Daolai Zhang, Chuan Ye, Tengwei Wang, Shen-Ming Huang, Jifei Han, Zihao Zhang, Junyan Gao, Mingxiang Zhang, Pu Zhao, Fengyang Li, Yongyuan Guo, Xiaojun Zhou, Cheng Xue Qin, Fan Yi, Xiao Yu, Wei Kong, Changtao Jiang, Jin‐Peng Sun · 发表于：Science · 年份：2025 · DOI：10.1126/science.ado4188 · 被引用次数：52 · 研究领域：Sphingolipid Metabolism and Signaling、S100 Proteins and Annexins、Estrogen and related hormone effects

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 G i 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 G i 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.