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

doi:10.1038/s42255-023-00794-y

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 journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Pages (from-to)	589-606
Number of pages	18
Journal	Nature Metabolism
Volume	5
Issue number	4
DOIs	https://doi.org/10.1038/s42255-023-00794-y
State	Published - Apr 2023

All Science Journal Classification (ASJC) codes

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

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Blair, M. C., Neinast, M. D., Jang, C., Chu, Q., Jung, J. W., Axsom, J., Bornstein, M. R., Thorsheim, C., Li, K., Hoshino, A., Yang, S., Roth Flach, R. J., Zhang, B. B., Rabinowitz, J. D., & Arany, Z. (2023). Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance. Nature Metabolism, 5(4), 589-606. https://doi.org/10.1038/s42255-023-00794-y

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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 = "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",

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Blair, MC, Neinast, MD, Jang, C, Chu, Q, Jung, JW, Axsom, J, Bornstein, MR, Thorsheim, C, Li, K, Hoshino, A, Yang, S, Roth Flach, RJ, Zhang, BB, Rabinowitz, JD & Arany, Z 2023, 'Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance', Nature Metabolism, vol. 5, no. 4, pp. 589-606. https://doi.org/10.1038/s42255-023-00794-y

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AU - Chu, Qingwei

AU - Jung, Jae Woo

AU - Axsom, Jessie

AU - Bornstein, Marc R.

AU - Thorsheim, Chelsea

AU - Li, Kristina

AU - Hoshino, Atsushi

AU - Yang, Steven

AU - Roth Flach, Rachel J.

AU - Zhang, Bei B.

AU - Rabinowitz, Joshua D.

AU - Arany, Zoltan

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

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