Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

中文翻译：

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棕色脂肪中的支链氨基酸氮通量控制代谢健康，与产热无关

棕色脂肪组织（BAT）以生热作用而闻名。啮齿动物研究表明，BAT 生热作用的增强与能量消耗的增加、体重的减轻和葡萄糖稳态的改善密切相关。然而，人类 BAT 具有预防 2 型糖尿病的作用，与体重无关。这种解离的机制尚不清楚。在这里，我们报告说，通过删除线粒体 BCAA 载体 (MBC)，BAT 中支链氨基酸 (BCAA) 的线粒体分解代谢受损，导致全身胰岛素抵抗，而不影响能量消耗和体重。棕色脂肪细胞在线粒体中分解代谢支链氨基酸，作为非必需氨基酸和谷胱甘肽生物合成的氮供体。 BAT 中线粒体 BCAA 氮通量受损会导致氧化应激增加、肝脏胰岛素信号传导减少以及循环 BCAA 衍生代谢物减少。高脂肪饮食减弱了 BAT 中的 BCAA 氮通量和代谢物合成，而冷激活的 BAT 则增强了合成。这项工作揭示了代谢物介导的途径，BAT 通过该途径控制产热之外的代谢健康。