Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism
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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.
in: CELL METAB, Jahrgang 20, Nr. 5, 04.11.2014, S. 898-909.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 L
AU - Smith, Richard D
AU - Qian, Wei-Jun
AU - Lynch, Christopher J
AU - Newgard, Christopher B
AU - Buettner, Christoph
N1 - Copyright © 2014 Elsevier Inc. All rights reserved.
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.
U2 - 10.1016/j.cmet.2014.09.003
DO - 10.1016/j.cmet.2014.09.003
M3 - SCORING: Journal article
C2 - 25307860
VL - 20
SP - 898
EP - 909
JO - CELL METAB
JF - CELL METAB
SN - 1550-4131
IS - 5
ER -