Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-03-13 DOI:10.1126/science.ado4188

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

{"title":"Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis","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","doi":"10.1126/science.ado4188","DOIUrl":null,"url":null,"abstract":"<div >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<sub>i</sub> 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<sub>i</sub> 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.</div>","PeriodicalId":21678,"journal":{"name":"Science","volume":"388 6746","pages":""},"PeriodicalIF":45.8000,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/science.ado4188","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

神经酰胺通过FPR2受体的代谢信号抑制脂肪细胞产热

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。在这项工作中，我们发现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G -环AMP信号通路抑制产热，在缺乏FPR2的情况下，这一作用被逆转。我们研究了FPR2与gi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。我们的发现为FPR2介导的脂肪细胞产热提供了结构基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

期刊介绍： Science is a leading outlet for scientific news, commentary, and cutting-edge research. Through its print and online incarnations, Science reaches an estimated worldwide readership of more than one million. Science’s authorship is global too, and its articles consistently rank among the world's most cited research. Science serves as a forum for discussion of important issues related to the advancement of science by publishing material on which a consensus has been reached as well as including the presentation of minority or conflicting points of view. Accordingly, all articles published in Science—including editorials, news and comment, and book reviews—are signed and reflect the individual views of the authors and not official points of view adopted by AAAS or the institutions with which the authors are affiliated. Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit recognition by the wider scientific community and general public provided by publication in Science, beyond that provided by specialty journals. Science welcomes submissions from all fields of science and from any source. The editors are committed to the prompt evaluation and publication of submitted papers while upholding high standards that support reproducibility of published research. Science is published weekly; selected papers are published online ahead of print.