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

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.

Citation

Qi-Xiang Ma, Wen-Ying Zhu, Xiao-Chen Lu, Duo Jiang, Feng Xu, Jin-Tao Li, Lei Zhang, Ying-Li Wu, Zheng-Jun Chen, Miao Yin, Hai-Yan Huang, Qun-Ying Lei. BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16. Nature metabolism. 2022 Jan;4(1):106-122

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PMID: 35075301

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