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

TitleThe adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
Publication TypeJournal Article
Year of Publication2021
AuthorsYu, 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
JournalCell Metab
Volume33
Issue5
Pagination905-922.e6
Date Published2021 May 04
ISSN1932-7420
Abstract

<p>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.</p>

DOI10.1016/j.cmet.2021.03.025
Alternate JournalCell Metab
PubMed ID33887198
PubMed Central IDPMC8102360
Grant ListF31 AG066311 / AG / NIA NIH HHS / United States
I01 BX004031 / BX / BLRD VA / United States
R01 AG056771 / AG / NIA NIH HHS / United States
P30 CA014520 / CA / NCI NIH HHS / United States
R21 AG061635 / AG / NIA NIH HHS / United States
R01 AG062328 / AG / NIA NIH HHS / United States
T32 AG000213 / AG / NIA NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States
R56 AG056771 / AG / NIA NIH HHS / United States
P30 AR066524 / AR / NIAMS NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 GM113142 / GM / NIGMS NIH HHS / United States