1. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine.
- Author
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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 3rd, Cheng EP, Konon EN, Haider LR, Finke M, Sonsalla M, Alexander CM, Rabinowitz JD, Baur JA, Malecki KC, and Lamming DW
- Subjects
- Adipose Tissue, White metabolism, Animals, Body Mass Index, Energy Metabolism, Fibroblast Growth Factors deficiency, Fibroblast Growth Factors genetics, Fibroblast Growth Factors metabolism, Humans, Liver metabolism, Male, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity metabolism, Obesity pathology, Protein Serine-Threonine Kinases metabolism, Uncoupling Protein 1 genetics, Uncoupling Protein 1 metabolism, Amino Acids, Branched-Chain metabolism, Diet veterinary, Isoleucine metabolism, Valine metabolism
- 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., Competing Interests: Declaration of interests D.W.L. has received funding from and is a scientific advisory board member of Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. UW-Madison has applied for a patent based in part on the findings reported here, for which N.E.R. and D.W.L. are inventors., (Published by Elsevier Inc.)
- Published
- 2021
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