Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids

Michael D. Neinast, Cholsoon Jang, Sheng Hui, Danielle S. Murashige, Qingwei Chu, Raphael J. Morscher, Xiaoxuan Li, Le Zhan, Eileen White, Tracy G. Anthony, Joshua D. Rabinowitz, Zoltan Arany

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)417-429.e4
JournalCell Metabolism
Volume29
Issue number2
DOIs
StatePublished - Feb 5 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Keywords

  • branched chain amino acids
  • insulin resistance
  • obesity
  • stable isotope tracing

Fingerprint Dive into the research topics of 'Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids'. Together they form a unique fingerprint.

Cite this