2025年3月13日出版的《科学》杂志发表了山东大学孙金鹏研究团队的最新成果，他们揭示了神经酰胺通过FPR2受体的代谢信号抑制脂肪细胞产热。

在这项工作中，小组发现FPR2是一种特异性结合长链神经酰胺（C14-C20）的膜受体。在棕色和米色脂肪细胞中，与FPR2结合的C16:0神经酰胺通过Gi-cyclic AMP信号通路抑制产热，在缺乏FPR2的情况下，这一作用被逆转。该研究团队研究了FPR2与G_i三聚体结合C16:0、C18:0和C20:0神经酰胺的三聚体的三个低温电镜结构。疏水尾部深嵌于正畸配体袋中，具有有限的可塑性。在密切相关的受体，如FPR1或FPR3中，神经酰胺结合基序的修饰可以将它们从无活性的神经酰胺受体转化为活性的神经酰胺受体。他们的发现为FPR2介导的脂肪细胞产热提供了结构基础。

研究人员表示，神经酰胺在人类健康和疾病中发挥着核心作用，但它们作为系统信号分子的作用仍然知之甚少。

附：英文原文

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

Author: 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

Issue&Volume: 2025-03-13

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 specifically binds long-chain ceramides (C14-C20). In brown and beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via Gi-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 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.

DOI: ado4188

Source: https://www.science.org/doi/10.1126/science.ado4188