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BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16.

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机构： [1]Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China. [2]Key Laboratory of Metabolism and Molecular Medicine of Chinese Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Fudan University, Shanghai, China. [3]Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore. [4]Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [5]Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [6]State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

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The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

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出版当年[2021]版：

大类 | 1 区

医学

小类 | 1 区内分泌学与代谢

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大类 | 1 区

医学

小类 | 1 区内分泌学与代谢

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第一作者机构： [1]Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, Shanghai Key Laboratory of Radiation Oncology, The Shanghai Key Laboratory of Medical Epigenetics, Department of Oncology, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China.

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