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Cell Metab. 2019 Feb 5;29(2):417-429.e4. doi: 10.1016/j.cmet.2018.10.013. Epub 2018 Nov 15.

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

Author information

1
Perelman School of Medicine, University of Pennsylvania, 3400 Civic Boulevard, Philadelphia, PA 19104, USA.
2
Perelman School of Medicine, University of Pennsylvania, 3400 Civic Boulevard, Philadelphia, PA 19104, USA; Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
3
Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
4
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
5
Department of Nutritional Sciences and the New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ 08901, USA.
6
Perelman School of Medicine, University of Pennsylvania, 3400 Civic Boulevard, Philadelphia, PA 19104, USA. Electronic address: zarany@pennmedicine.upenn.edu.

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:

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

PMID:
30449684
PMCID:
PMC6365191
[Available on 2020-02-05]
DOI:
10.1016/j.cmet.2018.10.013

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