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Title: Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism

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.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [4] ;  [4] ;  [5] ;  [5] ;  [6] ;  [7] ;  [2] ;  [2] ;  [8] ;  [4] ;  [1]
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States). Diabetes, Obesity, and Metabolism Inst. Dept. of Medicine
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  3. Icahn School of Medicine at Mount Sinai, New York, NY (United States). Diabetes, Obesity, and Metabolism Inst. Dept. of Medicine; Medical Univ. of Vienna (Austria)
  4. Duke Univ. Medical Center, Durham, NC (United States). Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Inst.
  5. Univ. of Ulm, Ulm (Germany). Dept. of General and Visceral Surgery
  6. Univ. Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Biochemistry and Molecular Cell Biology
  7. Oregon National Primate Research Center, Beaverton, OR (United States). Division of Diabetes, Obesity and Metabolism
  8. Pennsylvania State Univ. College of Medicine, Hershey, PA (United States). Cellular and Molecular Physiology
Publication Date:
OSTI Identifier:
1227559
Report Number(s):
PNNL-SA-103823
Journal ID: ISSN 1550-4131; 48135; 400412000
Grant/Contract Number:
AC05-76RL01830; DK074873; DK083568; DK082724; K01 DK099463; P51 OD011092; P41 GM103493; AC05-76RLO 1830
Type:
Published Article
Journal Name:
Cell Metabolism
Additional Journal Information:
Journal Volume: 20; Journal Issue: 5; Journal ID: ISSN 1550-4131
Publisher:
Cell Press
Research Org:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Environmental Molecular Sciences Laboratory