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Title | Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis. |
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Journal, issue, pages | Science, Page eado4188, Year 2025 |
Publish date | Mar 13, 2025 |
![]() | 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 / ![]() ![]() |
PubMed Abstract | 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 FPR2 as a membrane receptor that ...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 FPR2 as a membrane receptor that specifically binds long-chain ceramides (C14-C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via G-cyclic AMP 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 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. |
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Methods | EM (single particle) |
Resolution | 3.2 Å |
Structure data | EMDB-38964, PDB-8y62: EMDB-38965, PDB-8y63: EMDB-61484, PDB-9jhj: |
Chemicals | ![]() ChemComp-16C: ![]() PDB-1lxr: ![]() ChemComp-18C: |
Source |
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![]() | MEMBRANE PROTEIN / Ceramide / GPCR |