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

doi:10.1016/j.cmet.2014.09.003

Title: Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

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Abstract

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and 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 protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway in the liver. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptor expression in mice both demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeeding impairs the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in primates and obesity and/or type 2 diabetes in humans is associated with reduced BCKDH protein expression in liver, further supporting the concept that decreased hepatic BCKDH is a primary cause of increased plasma BCAA levels in insulin-resistant states. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and that hypothalamic insulin resistance can be a cause of impaired BCAA metabolism in obesity and diabetes.

Publication Date:: Sat Nov 01 00:00:00 EDT 2014

Research Org.:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Org.:: USDOE; National Institutes of Health (NIH)

OSTI Identifier:: 1227559

Alternate Identifier(s):: OSTI ID: 1166866

Report Number(s):: PNNL-SA-103823
Journal ID: ISSN 1550-4131; S1550413114004008; PII: S1550413114004008

Grant/Contract Number:: AC05-76RLO 1830; AC05-76RL01830; DK074873; DK083568; DK082724; K01 DK099463; P51 OD011092; P41 GM103493

Resource Type:: Published Article

Journal Name:: Cell Metabolism

Additional Journal Information:: Journal Name: Cell Metabolism Journal Volume: 20 Journal Issue: 5; Journal ID: ISSN 1550-4131

Publisher:: Elsevier

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory

Citation Formats


                    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 L., Smith, Richard D., Qian, Wei-Jun, Lynch, Christopher J., Newgard, Christopher B., and Buettner, Christoph. Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism.  United States: N. p., 2014. 
Web.  doi:10.1016/j.cmet.2014.09.003.

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                    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 L., 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.  United States.  https://doi.org/10.1016/j.cmet.2014.09.003

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                    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 L., Smith, Richard D., Qian, Wei-Jun, Lynch, Christopher J., Newgard, Christopher B., and Buettner, Christoph. Sat .  
"Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism".  United States.  https://doi.org/10.1016/j.cmet.2014.09.003.

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@article{osti_1227559,

  title        = {Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism},

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

  abstractNote = {Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and 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 protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway in the liver. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptor expression in mice both demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeeding impairs the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in primates and obesity and/or type 2 diabetes in humans is associated with reduced BCKDH protein expression in liver, further supporting the concept that decreased hepatic BCKDH is a primary cause of increased plasma BCAA levels in insulin-resistant states. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and that hypothalamic insulin resistance can be a cause of impaired BCAA metabolism in obesity and diabetes.},

  doi          = {10.1016/j.cmet.2014.09.003},

  journal      = {Cell Metabolism},

  number       = 5,

  volume       = 20,

  place        = {United States},

  year         = {Sat Nov 01 00:00:00 EDT 2014},

  month        = {Sat Nov 01 00:00:00 EDT 2014}

}

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