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 journalArticlepeer-review

181 Scopus citations


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 languageEnglish (US)
Pages (from-to)905-922.e6
JournalCell Metabolism
Issue number5
StatePublished - May 4 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Physiology
  • Cell Biology


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


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