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

TitleQuantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids.
Publication TypeJournal Article
Year of Publication2019
AuthorsNeinast, MD, Jang, C, Hui, S, Murashige, DS, Chu, Q, Morscher, RJ, Li, X, Zhan, L, White, E, Anthony, TG, Rabinowitz, JD, Arany, Z
JournalCell Metab
Volume29
Issue2
Pagination417-429.e4
Date Published2019 Feb 05
ISSN1932-7420
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.

DOI10.1016/j.cmet.2018.10.013
Alternate JournalCell Metab.
PubMed ID30449684
PubMed Central IDPMC6365191
Grant ListR01 DK114103 / DK / NIDDK NIH HHS / United States
R01 DK107667 / DK / NIDDK NIH HHS / United States
T32 GM007229 / GM / NIGMS NIH HHS / United States
R01 HL094499 / HL / NHLBI NIH HHS / United States
R01 DK109714 / DK / NIDDK NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States