美国霍华德休斯医学研究所Shingo Kajimura团队近期取得重要工作进展。他们研究提出，棕色脂肪中的BCAA-氮通量控制代谢健康不依赖于产热功能。相关研究成果2024年4月22日在线发表于《细胞》杂志上。
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。
总之，这一工作揭示了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。
附：英文原文
Title: BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis
Author: Anthony R.P. Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H. Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E. Gerszten, Evanna L. Mills, Alexander S. Banks, Yasushi Ishihama, Phillip J. White, Robert W. McGarrah, Takeshi Yoneshiro, Shingo Kajimura
Issue&Volume: 2024-04-22
Abstract: 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.
DOI: 10.1016/j.cell.2024.03.030
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00346-5