Perelman School of Medicine, University of Pennsylvania, 3400 Civic Boulevard, Philadelphia, PA 19104, USA.
Perelman School of Medicine, University of Pennsylvania, 3400 Civic Boulevard, Philadelphia, PA 19104, USA; Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
Cell Metab. 2019 Feb 5;29(2):417-429.e4. doi: 10.1016/j.cmet.2018.10.013. Epub 2018 Nov 15.
Elevations in branched-chain amino acids (BCAAs) associate with numerous systemic diseases, including cancer, diabetes, and heart failure. However, an integrated understanding of whole-body BCAA metabolism remains lacking. Here, we employ in vivo isotopic tracing to systemically quantify BCAA oxidation in healthy and insulin-resistant mice. We find that most tissues rapidly oxidize BCAAs into the tricarboxylic acid (TCA) cycle, with the greatest quantity occurring in muscle, brown fat, liver, kidneys, and heart. Notably, pancreas supplies 20% of its TCA carbons from BCAAs. Genetic and pharmacologic suppression of branched-chain alpha-ketoacid dehydrogenase kinase, a clinically targeted regulatory kinase, induces BCAA oxidation primarily in skeletal muscle of healthy mice. While insulin acutely increases BCAA oxidation in cardiac and skeletal muscle, chronically insulin-resistant mice show blunted BCAA oxidation in adipose tissues and liver, shifting BCAA oxidation toward muscle. Together, this work provides a quantitative framework for understanding systemic BCAA oxidation in health and insulin resistance.
支链氨基酸（BCAAs）的升高与许多全身性疾病有关，包括癌症、糖尿病和心力衰竭。然而，对全身 BCAA 代谢的综合理解仍然缺乏。在这里，我们采用体内同位素示踪法系统地定量测量健康和胰岛素抵抗小鼠中 BCAA 的氧化。我们发现大多数组织迅速将 BCAA 氧化成三羧酸（TCA）循环，其中肌肉、棕色脂肪、肝脏、肾脏和心脏的氧化量最大。值得注意的是，胰腺提供其 TCA 碳的 20%来自于 BCAA。临床上靶向调节激酶——支链α-酮酸脱氢酶激酶的遗传和药理学抑制，主要诱导健康小鼠的骨骼肌氧化 BCAA。虽然胰岛素急性增加心脏和骨骼肌中 BCAA 的氧化，但慢性胰岛素抵抗的小鼠在脂肪组织和肝脏中显示出 BCAA 氧化减弱，将 BCAA 氧化转向肌肉。总的来说，这项工作为理解健康和胰岛素抵抗状态下的全身 BCAA 氧化提供了一个定量框架。
