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

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

240 Scopus citations

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 (US)
Pages (from-to)	905-922.e6
Journal	Cell Metabolism
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2021.03.025
State	Published - May 4 2021

All Science Journal Classification (ASJC) codes

Physiology
Molecular Biology
Cell Biology

Keywords

FGF21
GCN2
body mass index
branched-chain amino acids
diabetes
insulin resistance
isoleucine
mTORC1
obesity
valine

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10.1016/j.cmet.2021.03.025

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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

@article{45b8dc6ffa894f2696057e617d734e40,

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

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.",

keywords = "FGF21, GCN2, body mass index, branched-chain amino acids, diabetes, insulin resistance, isoleucine, mTORC1, obesity, valine",

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

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = may,

day = "4",

doi = "10.1016/j.cmet.2021.03.025",

language = "English (US)",

volume = "33",

pages = "905--922.e6",

journal = "Cell Metabolism",

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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

TY - JOUR

T1 - The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine

AU - Yu, Deyang

AU - Richardson, Nicole E.

AU - Green, Cara L.

AU - Spicer, Alexandra B.

AU - Murphy, Michaela E.

AU - Flores, Victoria

AU - Jang, Cholsoon

AU - Kasza, Ildiko

AU - Nikodemova, Maria

AU - Wakai, Matthew H.

AU - Tomasiewicz, Jay L.

AU - Yang, Shany E.

AU - Miller, Blake R.

AU - Pak, Heidi H.

AU - Brinkman, Jacqueline A.

AU - Rojas, Jennifer M.

AU - Quinn, William J.

AU - Cheng, Eunhae P.

AU - Konon, Elizabeth N.

AU - Haider, Lexington R.

AU - Finke, Megan

AU - Sonsalla, Michelle

AU - Alexander, Caroline M.

AU - Rabinowitz, Joshua D.

AU - Baur, Joseph A.

AU - Malecki, Kristen C.

AU - Lamming, Dudley W.

PY - 2021/5/4

Y1 - 2021/5/4

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.

AB - 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.

KW - FGF21

KW - GCN2

KW - body mass index

KW - branched-chain amino acids

KW - diabetes

KW - insulin resistance

KW - isoleucine

KW - mTORC1

KW - obesity

KW - valine

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U2 - 10.1016/j.cmet.2021.03.025

DO - 10.1016/j.cmet.2021.03.025

M3 - Article

C2 - 33887198

AN - SCOPUS:85104907585

SN - 1550-4131

VL - 33

SP - 905-922.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

Abstract

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