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.
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Fasshauer
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Nika
authors.initials: N
authors.lastname: Filatova
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Linus A
authors.initials: LA
authors.lastname: Grundell
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Zielinski
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, WA 99352, USA.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scherer
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lindtner
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27710, USA.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: White
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27710, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Lapworth
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27710, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Ilkayeva
authors.affiliation: Department of General and Visceral Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
authors.affiliation: Department of General and Visceral Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wolf
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Scheja
authors.affiliation: Division of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, WA 99352, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Smith
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Boulevard, Richland, WA 99352, USA.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Qian
authors.affiliation: Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lynch
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27710, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Diabetes, Obesity, and Metabolism Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address: christoph.buettner@mssm.edu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Buettner
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000097:blood* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D017173:Caenorhabditis elegans; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D006943:Hyperglycemia / Q000097:blood / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D000597:Amino Acids, Branched-Chain; D007328:Insulin; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)