@article{67d2380db4364033b2def7db767889bb,
title = "Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance",
abstract = "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.",
author = "Blair, {Megan C.} and Neinast, {Michael D.} and Cholsoon Jang and Qingwei Chu and Jung, {Jae Woo} and Jessie Axsom and Bornstein, {Marc R.} and Chelsea Thorsheim and Kristina Li and Atsushi Hoshino and Steven Yang and {Roth Flach}, {Rachel J.} and Zhang, {Bei B.} and Rabinowitz, {Joshua D.} and Zoltan Arany",
note = "Funding Information: We thank R. Miller and K. Filipski for their feedback. M.C.B. was supported by a National Institutes of Health (NIH) grant no. F31DK132839. Z.A. was supported by NIH grant nos. DK114103 and CA248315. This work was also supported in part by Pfizer. We also thank the Penn Vector Core at the University of Pennsylvania for producing the custom AAV8 vectors, the Comparative Pathology Core at the University of Pennsylvania School of Veterinary Medicine for preparing and staining the mouse muscle slides, and J. Davis at the Rodent Metabolic Phenotyping Core, supported in part by Penn Diabetes Research Center grant nos. P30-DK19525 and S10-OD025098, for the lean mass body weight measurements. Metabolic studies were in part supported by NIH Diabetes Research Center grant no. P30 DK019525. Funding Information: R.J.R.F. and B.B.Z. are employees of Pfizer. This work was in part supported by Pfizer. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2023",
month = apr,
doi = "10.1038/s42255-023-00794-y",
language = "English (US)",
volume = "5",
pages = "589--606",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "4",
}