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

    Research output: Contribution to journalArticle

    49 Citations (Scopus)

    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
    StatePublished - Nov 4 2014

    Fingerprint

    Branched Chain Amino Acids
    3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
    Insulin
    Liver
    Brain
    Obesity
    Insulin Receptor
    Type 2 Diabetes Mellitus
    Primates
    Insulin Resistance
    Proteins
    Fats
    Enzymes

    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

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

    In: Cell Metabolism, Vol. 20, No. 5, 04.11.2014, p. 898-909.

    Research output: Contribution to journalArticle

    Shin, AC, Fasshauer, M, Filatova, N, Grundell, LA, Zielinski, E, Zhou, JY, Scherer, T, Lindtner, C, White, PJ, Lapworth, AL, Ilkayeva, O, Knippschild, U, Wolf, AM, Scheja, L, Grove, K, Smith, RD, Qian, WJ, Lynch, CJ, Newgard, CB & Buettner, C 2014, 'Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism', Cell Metabolism, vol. 20, no. 5, pp. 898-909. https://doi.org/10.1016/j.cmet.2014.09.003
    Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY et al. Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism. Cell Metabolism. 2014 Nov 4;20(5):898-909. https://doi.org/10.1016/j.cmet.2014.09.003
    Shin, Andrew C. ; Fasshauer, Martin ; Filatova, Nika ; Grundell, Linus A. ; Zielinski, Elizabeth ; Zhou, Jian Ying ; Scherer, Thomas ; Lindtner, Claudia ; White, Phillip J. ; Lapworth, Amanda L. ; Ilkayeva, Olga ; Knippschild, Uwe ; Wolf, Anna M. ; Scheja, Ludger ; Grove, Kevin ; Smith, Richard D. ; Qian, Wei Jun ; Lynch, Christopher J. ; Newgard, Christopher B. ; Buettner, Christoph. / Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism. In: Cell Metabolism. 2014 ; Vol. 20, No. 5. pp. 898-909.
    @article{82acaf6749ca4fe0a59a5406a9e8a218,
    title = "Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism",
    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.",
    author = "Shin, {Andrew C.} and Martin Fasshauer and Nika Filatova and Grundell, {Linus A.} and Elizabeth Zielinski and Zhou, {Jian Ying} and Thomas Scherer and Claudia Lindtner and White, {Phillip J.} and Lapworth, {Amanda L.} and Olga Ilkayeva and Uwe Knippschild and Wolf, {Anna M.} and Ludger Scheja and Kevin Grove and Smith, {Richard D.} and Qian, {Wei Jun} and Lynch, {Christopher J.} and Newgard, {Christopher B.} and Christoph Buettner",
    year = "2014",
    month = "11",
    day = "4",
    doi = "10.1016/j.cmet.2014.09.003",
    language = "English (US)",
    volume = "20",
    pages = "898--909",
    journal = "Cell Metabolism",
    issn = "1550-4131",
    publisher = "Cell Press",
    number = "5",

    }

    TY - JOUR

    T1 - Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism

    AU - Shin, Andrew C.

    AU - Fasshauer, Martin

    AU - Filatova, Nika

    AU - Grundell, Linus A.

    AU - Zielinski, Elizabeth

    AU - Zhou, Jian Ying

    AU - Scherer, Thomas

    AU - Lindtner, Claudia

    AU - White, Phillip J.

    AU - Lapworth, Amanda L.

    AU - Ilkayeva, Olga

    AU - Knippschild, Uwe

    AU - Wolf, Anna M.

    AU - Scheja, Ludger

    AU - Grove, Kevin

    AU - Smith, Richard D.

    AU - Qian, Wei Jun

    AU - Lynch, Christopher J.

    AU - Newgard, Christopher B.

    AU - Buettner, Christoph

    PY - 2014/11/4

    Y1 - 2014/11/4

    N2 - 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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84911002688&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84911002688&partnerID=8YFLogxK

    U2 - 10.1016/j.cmet.2014.09.003

    DO - 10.1016/j.cmet.2014.09.003

    M3 - Article

    VL - 20

    SP - 898

    EP - 909

    JO - Cell Metabolism

    JF - Cell Metabolism

    SN - 1550-4131

    IS - 5

    ER -