Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

Science. 2025 May;388(6746):eado4188. doi: 10.1126/science.ado4188. Epub 2025 May 1.

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 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.

MeSH terms

  • Adipocytes* / metabolism
  • Adipocytes, Brown* / metabolism
  • Adipocytes, Brown* / physiology
  • Animals
  • Ceramides* / chemistry
  • Ceramides* / metabolism
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Formyl Peptide* / chemistry
  • Receptors, Formyl Peptide* / genetics
  • Receptors, Formyl Peptide* / metabolism
  • Receptors, Lipoxin* / chemistry
  • Receptors, Lipoxin* / metabolism
  • Signal Transduction
  • Thermogenesis*

Substances

  • Ceramides
  • formyl peptide receptor 2, mouse
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • FPR2 protein, human