Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

• DOI: 10.1126/science.ado4188
• Publication Date: 2025-03-13T17:59:12Z
• Authors: Hui Lin; Chuanshun Ma; Kui Cai; Lulu Guo; Xuemei Wang; Lin Lv; Chao Zhang; Jun Lin; Daolai Zhang; Chuan Ye; Tengwei Wang; Shenming Huang; Jifei Han; Zihao Zhang; Junyan Gao; Mingxiang Zhang; Zhao Pu; Fengyang Li; Yongyuan Guo; Xiaojun Zhou; Chengxue Qin; Fan Yi; Xiao Yu; Wei Kong; Changtao Jiang; Jin-Peng Sun

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.