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Cell Metab
2021 Apr 16;S1550-4131(21)00166-2.
doi: 10.1016/j.cmet.2021.03.025.
Online ahead of print.
The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine
Deyang Yu 1 ,
Nicole E Richardson 2 ,
Cara L Green 3 ,
Alexandra B Spicer 4 ,
Michaela E Murphy 5 ,
Victoria Flores 5 ,
Cholsoon Jang 6 ,
Ildiko Kasza 7 ,
Maria Nikodemova 4 ,
Matthew H Wakai 3 ,
Jay L Tomasiewicz 8 ,
Shany E Yang 3 ,
Blake R Miller 3 ,
Heidi H Pak 3 ,
Jacqueline A Brinkman 3 ,
Jennifer M Rojas 9 ,
William J Quinn 3rd 9 ,
Eunhae P Cheng 3 ,
Elizabeth N Konon 3 ,
Lexington R Haider 3 ,
Megan Finke 3 ,
Michelle Sonsalla 3 ,
Caroline M Alexander 7 ,
Joshua D Rabinowitz 10 ,
Joseph A Baur 9 ,
Kristen C Malecki 4 ,
Dudley W Lamming 11
Affiliations
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.
2021 Apr 16;S1550-4131(21)00166-2.
doi: 10.1016/j.cmet.2021.03.025.
Online ahead of print.
The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine
Deyang Yu 1 ,
Nicole E Richardson 2 ,
Cara L Green 3 ,
Alexandra B Spicer 4 ,
Michaela E Murphy 5 ,
Victoria Flores 5 ,
Cholsoon Jang 6 ,
Ildiko Kasza 7 ,
Maria Nikodemova 4 ,
Matthew H Wakai 3 ,
Jay L Tomasiewicz 8 ,
Shany E Yang 3 ,
Blake R Miller 3 ,
Heidi H Pak 3 ,
Jacqueline A Brinkman 3 ,
Jennifer M Rojas 9 ,
William J Quinn 3rd 9 ,
Eunhae P Cheng 3 ,
Elizabeth N Konon 3 ,
Lexington R Haider 3 ,
Megan Finke 3 ,
Michelle Sonsalla 3 ,
Caroline M Alexander 7 ,
Joshua D Rabinowitz 10 ,
Joseph A Baur 9 ,
Kristen C Malecki 4 ,
Dudley W Lamming 11
Affiliations
- PMID: 33887198
- DOI: 10.1016/j.cmet.2021.03.025
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.
