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 L. Grove; Richard D. Smith; Wei Jun Qian; Christopher J. Lynch; Christopher B. Newgard; Christoph Buettner

doi:10.1016/j.cmet.2014.09.003

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 L. Grove, Richard D. Smith, Wei Jun Qian, Christopher J. Lynch, Christopher B. Newgard, Christoph Buettner

Research output: Contribution to journal › Article › peer-review

98 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 language	English (US)
Pages (from-to)	898-909
Number of pages	12
Journal	Cell Metabolism
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2014.09.003
State	Published - Nov 4 2014
Externally published	Yes

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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Shin, A. C., Fasshauer, M., Filatova, N., Grundell, L. A., Zielinski, E., Zhou, J. Y., Scherer, T., Lindtner, C., White, P. J., Lapworth, A. L., Ilkayeva, O., Knippschild, U., Wolf, A. M., Scheja, L., Grove, K. L., Smith, R. D., Qian, W. J., Lynch, C. J., Newgard, C. B., & 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

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, KL, 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

@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 Grove, {Kevin L.} and Smith, {Richard D.} and Qian, {Wei Jun} and Lynch, {Christopher J.} and Newgard, {Christopher B.} and Christoph Buettner",

note = "Funding Information: We would like to thank James D. O{\textquoteright}Hare, Tiffany Chi, Seta Degann, Brian Closs, Adam Spitz, and Lee Honig for their technical assistance and Dr. Charles V. Mobbs and Elizabeth Schwartz for help with the C. elegans study. This study was supported by NIH grants DK074873, DK083568, DK082724 (C.B.), K01 DK099463 (A.C.S.), P51 OD011092 (K.L.G.), and P41 GM103493 (R.D.S.) and by the Boehringer Ingelheim Foundation (M.F.). Proteomic analysis was performed in the Environmental Molecular Sciences Laboratory (EMSL), a DOE national scientific user facility located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute under contract DE-AC05-76RLO 1830. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

month = nov,

day = "4",

doi = "10.1016/j.cmet.2014.09.003",

language = "English (US)",

volume = "20",

pages = "898--909",

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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 L.

AU - Smith, Richard D.

AU - Qian, Wei Jun

AU - Lynch, Christopher J.

AU - Newgard, Christopher B.

AU - Buettner, Christoph

N1 - Funding Information: We would like to thank James D. O’Hare, Tiffany Chi, Seta Degann, Brian Closs, Adam Spitz, and Lee Honig for their technical assistance and Dr. Charles V. Mobbs and Elizabeth Schwartz for help with the C. elegans study. This study was supported by NIH grants DK074873, DK083568, DK082724 (C.B.), K01 DK099463 (A.C.S.), P51 OD011092 (K.L.G.), and P41 GM103493 (R.D.S.) and by the Boehringer Ingelheim Foundation (M.F.). Proteomic analysis was performed in the Environmental Molecular Sciences Laboratory (EMSL), a DOE national scientific user facility located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute under contract DE-AC05-76RLO 1830. Publisher Copyright: © 2014 Elsevier Inc.

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.

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JF - Cell Metabolism

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ER -

Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism

Abstract

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