Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance

Megan C. Blair, Michael D. Neinast, Cholsoon Jang, Qingwei Chu, Jae Woo Jung, Jessie Axsom, Marc R. Bornstein, Chelsea Thorsheim, Kristina Li, Atsushi Hoshino, Steven Yang, Rachel J. Roth Flach, Bei B. Zhang, Joshua D. Rabinowitz, Zoltan Arany

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Elevated levels of plasma branched-chain amino acids (BCAAs) have been associated with insulin resistance and type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves insulin sensitivity. Here we show that modulation of BCKDH in skeletal muscle, but not liver, affects fasting plasma BCAAs in male mice. However, despite lowering BCAAs, increased BCAA oxidation in skeletal muscle does not improve insulin sensitivity. Our data indicate that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. These findings suggest potential concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.

Original languageEnglish (US)
Pages (from-to)589-606
Number of pages18
JournalNature Metabolism
Issue number4
StatePublished - Apr 2023

All Science Journal Classification (ASJC) codes

  • Physiology (medical)
  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology


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