Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids. Author Michael Neinast, Cholsoon Jang, Sheng Hui, Danielle Murashige, Qingwei Chu, Raphael Morscher, Xiaoxuan Li, Le Zhan, Eileen White, Tracy Anthony, Joshua Rabinowitz, Zoltan Arany Publication Year 2019 Type Journal Article Abstract 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. Keywords Animals, Mice, Mice, Inbred C57BL, Citric Acid Cycle, Male, Insulin, Oxidation-Reduction, Myocardium, Amino Acids, Branched-Chain, Insulin Resistance, Muscle, Skeletal, Obesity, Liver, Adipose Tissue, Brown Journal Cell Metab Volume 29 Issue 2 Pages 417-429.e4 Date Published 2019 Feb 05 ISSN Number 1932-7420 DOI 10.1016/j.cmet.2018.10.013 Alternate Journal Cell Metab PMCID PMC6365191 PMID 30449684 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML