Mapping And Directing Branched-Chain Amino Acid Metabolism In Health And Insulin Resistance

Abstract

Unbiased metabolomics studies in human serum have identified changes in branched-chain amino acid (BCAA) levels as biomarkers of diabetes, heart failure, and some forms of cancer. However, the changes in BCAA metabolism in each of these cases, and even in the normal state, have remained elusive. Using novel heavy-isotope infusions, I quantified whole-body BCAA metabolism in healthy mice, establishing a foundation for understanding BCAA metabolism. Most tissues supply 1-5% of their TCA carbons from BCAAs, but the pancreas supplies 20% of its TCA carbons from BCAAs. Novel modeling of whole-body metabolic flux indicates the greatest portion of systemic BCAA oxidation occurs in skeletal muscle, brown fat, and liver. Genetic and pharmacologic suppression of branched-chain alpha-ketoacid dehydrogenase kinase, a 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. Pharmacologic activation of BCAA oxidation in diabetic mice reduced plasma BCAAs and slightly improved insulin sensitivity but did not reverse diabetes. In contrast, genetic activation of BCAA oxidation specifically in skeletal muscle had no impact on glucose tolerance or insulin sensitivity even though plasma BCAAs were reduced. Together, this work provides a quantitative framework for understanding BCAA metabolism, suggests that activation of BCAA oxidation in some tissue other than skeletal muscle improves insulin sensitivity, and decouples the plasma BCAA concentration from insulin resistance