2024年4月22日，来自美国霍华德休斯医学研究所Shingo Kajimura团队在《细胞》杂志上发表了标题为“BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.”的研究成果，发现棕色脂肪中的BCAA-氮通量控制代谢健康不依赖于产热功能。
据介绍，棕色脂肪组织（BAT）具有产热作用。啮齿动物研究表明，BAT产热增强与能量消耗增加、体重减轻和葡萄糖稳态改善密切相关。然而，人类BAT对2型糖尿病具有保护作用，与体重无关。这种分离的机制尚不清楚。
研究人员报道了BAT中支链氨基酸（BCAA）的线粒体分解代谢受损，通过删除线粒体BCAA载体（MBC），在不影响能量消耗和体重的情况下引起全身胰岛素抵抗。棕色脂肪细胞在线粒体中分解代谢BCAA，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氮通量受损导致氧化应激增加，肝脏胰岛素信号传导减少，循环BCAA来源代谢产物减少。高脂肪饮食减弱了BAT中BCAA氮通量和代谢产物的合成，而冷激活的BAT增强了合成。
棕色脂肪组织（BAT）中支链氨基酸（BCAA）的代谢独立于能耗和体重，其作为含氮代谢物的氮供体而非TCA循环燃料调节代谢健康。BCAA衍生的含氮代谢物可调节全身氧化还原平衡及葡萄糖稳态，其减少会导致胰岛素抵抗。这一发现揭示了BAT代谢益处的新机制，并为研究复杂代谢生物学问题提供了新工具。这一种代谢产物介导的途径，BAT通过该途径控制产热作用之外的代谢健康。
Highlights
- BCAA is a key nitrogen source for synthesizing non-essential amino acids and GSH
- Mitochondrial BCAA import via MBC is required for BCAA-derived metabolite synthesis
- Reduced synthesis of BCAA-derived metabolites in BAT results in insulin resistance
- Obesity impairs BCAA-nitrogen flux and BCAA-derived metabolite synthesis in BAT
Summary
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.
文章来源：
Anthony R.P. Verkerke, Dandan Wang et al, BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.DOI: 10.1016/j.cell.2024.03.030，Cell：最新IF：66.85
