Branched chain amino acids (BCAAs) are associated with the progression of obesity-related metabolic disorders, including type 2 diabetes and nonalcoholic fatty liver disease. However, whether BCAAs disrupt the homeostasis of hepatic glucose and lipid metabolism remains unknown. In this study, we observed that BCAAs supplementation significantly reduced high-fat (HF) diet–induced hepatic lipid accumulation while increasing the plasma lipid levels and promoting muscular and renal lipid accumulation. Further studies demonstrated that BCAAs supplementation significantly increased hepatic gluconeogenesis and suppressed hepatic lipogenesis in HF diet-induced obese (DIO) mice. These phenotypes resulted from severe attenuation of Akt2 signaling via mTORC1- and mTORC2-dependent pathways. BCAAs/branched-chain α-keto acids (BCKAs) chronically suppressed Akt2 activation through mTORC1 and mTORC2 signaling and promoted Akt2 ubiquitin-proteasome–dependent degradation through the mTORC2 pathway. Moreover, the E3 ligase Mul1 played an essential role in BCAAs/BCKAs-mTORC2-induced Akt2 ubiquitin-dependent degradation. We also demonstrated that BCAAs inhibited hepatic lipogenesis by blocking Akt2/SREBP1/INSIG2a signaling and increased hepatic glycogenesis by regulating Akt2/Foxo1 signaling. Collectively, these data demonstrate that in DIO mice, BCAAs supplementation resulted in serious hepatic metabolic disorder and severe liver insulin resistance: insulin failed to not only suppress gluconeogenesis but also activate lipogenesis. Intervening BCAA metabolism is a potential therapeutic target for severe insulin-resistant disease.

中文翻译：

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支链氨基酸通过减弱 Akt2 信号传导加剧与肥胖相关的肝葡萄糖和脂质代谢紊乱

支链氨基酸 (BCAA) 与肥胖相关代谢紊乱的进展有关，包括 2 型糖尿病和非酒精性脂肪肝。然而，支链氨基酸是否会破坏肝脏葡萄糖和脂质代谢的稳态仍然未知。在这项研究中，我们观察到补充支链氨基酸显着减少高脂肪 (HF) 饮食诱导的肝脏脂质积累，同时增加血浆脂质水平并促进肌肉和肾脏脂质积累。进一步的研究表明，在 HF 饮食诱导的肥胖 (DIO) 小鼠中，补充支链氨基酸显着增加了肝脏糖异生并抑制了肝脏脂肪生成。这些表型是由于 Akt2 信号通过 mTORC1 和 mTORC2 依赖性途径严重减弱所致。BCAAs/支链α-酮酸（BCKAs）通过 mTORC1 和 mTORC2 信号传导长期抑制 Akt2 活化，并通过 mTORC2 途径促进 Akt2 泛素蛋白酶体依赖性降解。此外，E3 连接酶 Mul1 在 BCAAs/BCKAs-mTORC2 诱导的 Akt2 泛素依赖性降解中发挥了重要作用。我们还证明，BCAAs 通过阻断 Akt2/SREBP1/INSIG2a 信号传导抑制肝脏脂肪生成，并通过调节 Akt2/Foxo1 信号传导增加肝糖生成。总的来说，这些数据表明，在 DIO 小鼠中，补充支链氨基酸会导致严重的肝脏代谢紊乱和严重的肝脏胰岛素抵抗：胰岛素不仅不能抑制糖异生，还不能激活脂肪生成。干预 BCAA 代谢是严重胰岛素抵抗疾病的潜在治疗目标。