Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism

Andrew C. Shin, Martin Fasshauer, Nika Filatova, Linus A. Grundell, Elizabeth Zielinski, Jian Ying Zhou, Thomas Scherer, Claudia Lindtner, Phillip J. White, Amanda L. Lapworth, Olga Ilkayeva, Uwe Knippschild, Anna M. Wolf, Ludger Scheja, Kevin Grove, Richard D. Smith, Wei Jun Qian, Christopher J. Lynch, Christopher B. Newgard, Christoph Buettner

    58 Scopus citations

    Abstract

    Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

    Original languageEnglish (US)
    Pages (from-to)898-909
    Number of pages12
    JournalCell Metabolism
    Volume20
    Issue number5
    DOIs
    Publication statusPublished - Nov 4 2014

    ASJC Scopus subject areas

    • Cell Biology
    • Molecular Biology
    • Physiology

    Cite this

    Shin, A. C., Fasshauer, M., Filatova, N., Grundell, L. A., Zielinski, E., Zhou, J. Y., ... Buettner, C. (2014). Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism. Cell Metabolism, 20(5), 898-909. https://doi.org/10.1016/j.cmet.2014.09.003