Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids.
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.
['Neinast|Michael D|MD|', 'Jang|Cholsoon|C|', 'Hui|Sheng|S|', 'Murashige|Danielle S|DS|', 'Chu|Qingwei|Q|', 'Morscher|Raphael J|RJ|', 'Li|Xiaoxuan|X|', 'Zhan|Le|L|', 'White|Eileen|E|', 'Anthony|Tracy G|TG|', 'Rabinowitz|Joshua D|JD|', 'Arany|Zoltan|Z|']
D002001:Adipose Tissue, Brown D000597:Amino Acids, Branched-Chain D000818:Animals D002952:Citric Acid Cycle D007328:Insulin D007333:Insulin Resistance D008099:Liver D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018482:Muscle, Skeletal D009206:Myocardium D009765:Obesity D010084:Oxidation-Reduction
insulin resistance branched chain amino acids obesity stable isotope tracing