Title | The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | 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 |
Journal | Cell Metab |
Volume | 33 |
Issue | 5 |
Pagination | 905-922.e6 |
Date Published | 2021 May 04 |
ISSN | 1932-7420 |
Keywords | Adipose Tissue, White, Amino Acids, Branched-Chain, Animals, Body Mass Index, Diet, Energy Metabolism, Fibroblast Growth Factors, Humans, Isoleucine, Liver, Male, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Protein Serine-Threonine Kinases, Uncoupling Protein 1, Valine |
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> |
DOI | 10.1016/j.cmet.2021.03.025 |
Alternate Journal | Cell Metab |
PubMed ID | 33887198 |
PubMed Central ID | PMC8102360 |
Grant List | F31 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 |