Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell metabolism, 2019-02, Vol.29 (2), p.417-429.e4

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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. [Display omitted] •In vivo isotope tracing provides a quantitative framework of tissue BCAA oxidation•Genetic and pharmacological perturbations alter the distribution of BCAA oxidation•Insulin acutely increases BCAA oxidation selectively in striated muscle•Insulin-resistant mice shunt BCAA oxidation from liver and fat towards muscle Increases in branched-chain amino acids (BCAAs) have been associated with diabetes, cancer, and heart failure. Here, Neinast et al. use in vivo isotopic tracing to provide an integrated overview of whole-body BCAA metabolism. A shift in BCAA oxidation away from adipocytes and liver, toward muscle, is seen in insulin resistance.