BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16
BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16
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BCAA–BCKA 轴通过 PRDM16 乙酰化调节 WAT 褐变
DOI：
10.1038/s42255-021-00520-6
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发表时间：
2022-01-24
影响因子：
20.8
通讯作者：
Lei, Qun-Ying
中科院分区：
文献类型：
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作者：
Ma, Qi-Xiang;Zhu, Wen-Ying;Lei, Qun-Ying
支链氨基酸（BCAA）和肥胖之间的联系已经知道了几十年，但BCAA代谢在肥胖个体的白色脂肪组织（WAT）中的功能作用仍然模糊。在这里，我们表明，与脂肪组织敲除的Bcat 2，它转换支链氨基酸支链酮酸（BCKAs），小鼠是抵抗高脂肪饮食诱导的肥胖，由于增加腹股沟WAT布朗宁和产热。从机制上讲，BCKA衍生的乙酰辅酶A通过在K915处乙酰化含有PR结构域的蛋白16（PRDM 16），破坏PRDM 16和过氧化物酶体增殖物激活受体-γ（PPARγ）之间的相互作用以维持WAT特性来抑制WAT布朗宁。BCKA衍生的乙酰辅酶A的消耗强烈地促进WAT布朗宁和能量消耗。相反，BCKA补充剂在Bcat 2敲除小鼠中重新建立了高脂饮食诱导的肥胖。此外，替米沙坦（一种抗高血压药物）通过直接结合显著抑制Bcat 2活性，导致WAT布朗宁增强和肥胖减少。引人注目的是，补充BCKA逆转了替米沙坦赋予的瘦表型。因此，我们揭示了BCAA-BCKA轴在WAT布朗宁中的关键作用。
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 inBcat2knockout 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.