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