Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis PMID: 40080544

GLP-1 and Obesity Research

2026-08-18

Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

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

Hui Lin ^# ¹ ² ³ , Chuanshun Ma ^# ⁴ , Kui Cai ^# ² , Lulu Guo ^# ¹ ⁵ , Xuemei Wang ^# ² , Lin Lv ^# ⁶ , Chao Zhang ^# ⁶ , Jun Lin ^# ² , Daolai Zhang ⁷ , Chuan Ye ² , Tengwei Wang ¹ , Shenming Huang ¹ , Jifei Han ⁴ , Zihao Zhang ⁴ , Junyan Gao ³ , Mingxiang Zhang ⁷ , Zhao Pu ⁴ ⁸ , Fengyang Li ⁹ , Yongyuan Guo ¹⁰ , Xiaojun Zhou ⁹ , Chengxue Qin ⁹ , Fan Yi ¹¹ , Xiao Yu ⁴ , Wei Kong ² ¹² , Changtao Jiang ² ¹³ , Jin-Peng Sun ¹ ² ⁶ ¹⁴

Affiliations

1. New Cornerstone Science Laboratory, Advanced Medical Research Institute, and NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
3. Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong, China.
4. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
5. Key Laboratory of Membrane Receptor Drug Target Discovery and Lead Drug Screening at Shandong Province, Shandong, China.
6. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
7. School of Pharmacy, Binzhou Medical University, Yantai, China.
8. Department of Biochemistry and Human Biology, University of Toronto, Toronto, Ontario, Canada.
9. School of Pharmacy, Shandong University, Jinan, Shandong, China.
10. Department of Orthopaedics, Qilu Hospital of Shandong University, Jinan, Shandong, China.
11. Key Laboratory of Infection and Immunity of Shandong Province, Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, China.
12. Department of Cardiology, Peking University First Hospital, Beijing, China.
13. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
14. Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
# Contributed equally.

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 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.