{"title":"1-Linoleoylglycerophosphocholine stimulates UCP1-dependent thermogenesis and mitochondrial respiration to combat obesity.","authors":"Rui Wang, Tianfu Zhu, Jingxian Lu, Mengke Cheng, Xingyun Wang, Xirong Guo, Shan Huang, Jianfang Gao","doi":"10.1016/j.jlr.2025.100914","DOIUrl":null,"url":null,"abstract":"<p><p>Obesity leads to numerous illnesses and metabolic disorders, with lysophosphatidylcholine (LPC) levels declining in obese patients. However, the physiological role of LPC and the regulatory mechanisms involved in modulating obesity remain largely unknown. Here, we provide evidence that 1-linoleoylglycerophosphocholine (1-LGPC) promotes adipocyte energy expenditure by activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) axis. Metabolomic analyses identified 1-LGPC as a characteristic metabolite that declined in the peripheral blood of obese patients. Treatment with 1-LGPC effectively alleviated high-fat diet-induced lipid accumulation in zebrafish larvae and human adipocytes. Elevated expression levels, increased oxygen consumption rates, and enhanced transcript levels indicated that uncoupling protein 1-dependent thermogenesis and mitochondrial respiration were significantly boosted. Furthermore, NRF2 expression and nuclear translocation were induced by 1-LGPC, and NRF2 inhibition triggered UCP1 downregulation and lipid accumulation restoration, confirming the KEAP1-NRF2 axis's involvement in 1-LGPC-induced energy expenditure. These findings offer preliminary insights into physiological roles and mechanisms by which 1-LGPC modulates lipid and energy metabolism, providing potential strategies for obesity intervention using clinically identified compounds.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100914"},"PeriodicalIF":4.1000,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Lipid Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jlr.2025.100914","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Obesity leads to numerous illnesses and metabolic disorders, with lysophosphatidylcholine (LPC) levels declining in obese patients. However, the physiological role of LPC and the regulatory mechanisms involved in modulating obesity remain largely unknown. Here, we provide evidence that 1-linoleoylglycerophosphocholine (1-LGPC) promotes adipocyte energy expenditure by activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) axis. Metabolomic analyses identified 1-LGPC as a characteristic metabolite that declined in the peripheral blood of obese patients. Treatment with 1-LGPC effectively alleviated high-fat diet-induced lipid accumulation in zebrafish larvae and human adipocytes. Elevated expression levels, increased oxygen consumption rates, and enhanced transcript levels indicated that uncoupling protein 1-dependent thermogenesis and mitochondrial respiration were significantly boosted. Furthermore, NRF2 expression and nuclear translocation were induced by 1-LGPC, and NRF2 inhibition triggered UCP1 downregulation and lipid accumulation restoration, confirming the KEAP1-NRF2 axis's involvement in 1-LGPC-induced energy expenditure. These findings offer preliminary insights into physiological roles and mechanisms by which 1-LGPC modulates lipid and energy metabolism, providing potential strategies for obesity intervention using clinically identified compounds.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.