The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Deyang Yu; Nicole E. Richardson; Cara L. Green; Alexandra B. Spicer; Michaela E. Murphy; Victoria Flores; Cholsoon Jang; Ildiko Kasza; Maria Nikodemova; Matthew H. Wakai; Jay L. Tomasiewicz; Shany E. Yang; Blake R. Miller; Heidi H. Pak; Jacqueline A. Brinkman; Jennifer M. Rojas; William J. Quinn; Eunhae P. Cheng; Elizabeth N. Konon; Lexington R. Haider; Megan Finke; Michelle Sonsalla; Caroline M. Alexander; Joshua D. Rabinowitz; Joseph A. Baur; Kristen C. Malecki; Dudley W. Lamming

doi:10.1016/j.cmet.2021.03.025

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Deyang Yu, Nicole E. Richardson, Cara L. Green, Alexandra B. Spicer, Michaela E. Murphy, Victoria Flores, Cholsoon Jang, Ildiko Kasza, Maria Nikodemova, Matthew H. Wakai, Jay L. Tomasiewicz, Shany E. Yang, Blake R. Miller, Heidi H. Pak, Jacqueline A. Brinkman, Jennifer M. Rojas, William J. Quinn, Eunhae P. Cheng, Elizabeth N. Konon, Lexington R. HaiderMegan Finke, Michelle Sonsalla, Caroline M. Alexander, Joshua D. Rabinowitz, Joseph A. Baur, Kristen C. Malecki, Dudley W. Lamming

Department for Health

Research output: Contribution to journal › Article › peer-review

328 Citations (SciVal)

Abstract

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

Original language	English
Pages (from-to)	905-922.e6
Number of pages	25
Journal	Cell Metabolism
Volume	33
Issue number	5
Early online date	21 Apr 2021
DOIs	https://doi.org/10.1016/j.cmet.2021.03.025
Publication status	Published - 4 May 2021

Data Availability Statement

The accession number for the gene expression data reported in this paper can be obtained from Gene Expression Omnibus (GEO)
(GEO: GSE168588).

Acknowledgements

We would like to thank Dr. Dawn Davis and Dr. Vincent Cryns for their valuable insights and comments. We thank Dr. Tina Herfel (Envigo) for assistance with
diet formulation. The MANLAC2 (10F8) antibody was developed by G.E. Morris
and was obtained from the Developmental Studies Hybridoma Bank, created
by the NICHD of the NIH, and maintained at the University of Iowa, Department
of Biology, Iowa City, IA 52242.

Funding

The work was supported in part by the NIH/NIA (AG056771, AG062328, and AG061635 to D.W.L.), the NIH/NIGMS (GM113142 to C.M.A.), the NIH/NIAMS (P30 AR066524 Pilot Award to I.K.), the NIH/NIDDK (DP1DK113643 to J.D.R.), a Glenn Foundation Award for Research in the Biological Mechanisms of Aging to D.W.L., and startup funds from the UW-Madison School of Medicine and Public Health and Department of Medicine to D.W.L. Support for this research was provided by the UW-Madison Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation. The Survey of the Health of Wisconsin is funded by the Wisconsin Partnership Program. This research was conducted while D.W.L. was an AFAR Research Grant recipient from the American Federation for Aging Research. D.Y. was supported in part by a fellowship from the American Heart Association (17PRE33410983). N.E.R. was supported in part by a training grant from the UW Institute on Aging (NIA T32 AG000213). C.L.G. was supported in part by a grant from Dalio Philanthropies and is supported by a Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research. V.F. and M.E.M. were supported in part by Research Supplements to Promote Diversity in Health-Related Research (R01 AG056771-01A1S1 and R01AG062328-03S1). H.H.P. was supported in part by a NIA F31 predoctoral fellowship (AG066311). I.K. was supported in part by McArdle Departmental Funds. C.J. was supported by the American Diabetes Association (1-17-PDF-076). Metabolomics work was supported by Diabetes Research Center grant P30 DK019525. The UW Carbone Cancer Center (UWCCC) Experimental Pathology Laboratory is supported by P30 CA014520 from the NIH/NCI. Clamp studies were performed in the Rodent Metabolic Phenotyping Core of the University of Pennsylvania Diabetes Research Center (P30 DK19525); this award also supported in part the metabolomics analysis. This work was supported in part by the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adipose Tissue, White/metabolism
Amino Acids, Branched-Chain/metabolism
Animals
Body Mass Index
Diet/veterinary
Energy Metabolism
Fibroblast Growth Factors/deficiency
Humans
Isoleucine/metabolism
Liver/metabolism
Male
Mechanistic Target of Rapamycin Complex 1/metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity/metabolism
Protein Serine-Threonine Kinases/metabolism
Uncoupling Protein 1/genetics
Valine/metabolism

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

Access to Document

10.1016/j.cmet.2021.03.025

Cite this

Yu, D., Richardson, N. E., Green, C. L., Spicer, A. B., Murphy, M. E., Flores, V., Jang, C., Kasza, I., Nikodemova, M., Wakai, M. H., Tomasiewicz, J. L., Yang, S. E., Miller, B. R., Pak, H. H., Brinkman, J. A., Rojas, J. M., Quinn, W. J., Cheng, E. P., Konon, E. N., ... Lamming, D. W. (2021). The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metabolism, 33(5), 905-922.e6. https://doi.org/10.1016/j.cmet.2021.03.025

Yu, D, Richardson, NE, Green, CL, Spicer, AB, Murphy, ME, Flores, V, Jang, C, Kasza, I, Nikodemova, M, Wakai, MH, Tomasiewicz, JL, Yang, SE, Miller, BR, Pak, HH, Brinkman, JA, Rojas, JM, Quinn, WJ, Cheng, EP, Konon, EN, Haider, LR, Finke, M, Sonsalla, M, Alexander, CM, Rabinowitz, JD, Baur, JA, Malecki, KC & Lamming, DW 2021, 'The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine', Cell Metabolism, vol. 33, no. 5, pp. 905-922.e6. https://doi.org/10.1016/j.cmet.2021.03.025

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abstract = "Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.",

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AU - Flores, Victoria

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AU - Kasza, Ildiko

AU - Nikodemova, Maria

AU - Wakai, Matthew H.

AU - Tomasiewicz, Jay L.

AU - Yang, Shany E.

AU - Miller, Blake R.

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AU - Sonsalla, Michelle

AU - Alexander, Caroline M.

AU - Rabinowitz, Joshua D.

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N2 - Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

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SP - 905-922.e6

JO - Cell Metabolism

JF - Cell Metabolism

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ER -

The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

Abstract

Data Availability Statement

Acknowledgements

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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