Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism

被引：114

作者：

Shin, Andrew C. ^{[1
]}

Fasshauer, Martin ^{[1
]}

Filatova, Nika ^{[1
]}

Grundell, Linus A. ^{[1
]}

Zielinski, Elizabeth ^{[1
]}

Zhou, Jian-Ying ^{[2
]}

Scherer, Thomas ^{[1
]}

Lindtner, Claudia ^{[1
]}

White, Phillip J. ^{[3
,4
]}

Lapworth, Amanda L. ^{[3
,4
]}

Ilkayeva, Olga ^{[3
,4
]}

Knippschild, Uwe ^{[5
]}

Wolf, Anna M. ^{[5
]}

Scheja, Ludger ^{[6
]}

Grove, Kevin L. ^{[7
]}

Smith, Richard D. ^{[2
]}

Qian, Wei-Jun ^{[2
]}

Lynch, Christopher J. ^{[8
]}

Newgard, Christopher B. ^{[3
,4
]}

Buettner, Christoph ^{[1
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Med, Diabet Obes & Metab Inst, New York, NY 10029 USA

[2] Pacific NW Natl Lab, Biol Sci Div, Richland, WA 99352 USA

[3] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27710 USA

[4] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27710 USA

[5] Univ Ulm, Dept Gen & Visceral Surg, D-89081 Ulm, Germany

[6] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, D-20246 Hamburg, Germany

[7] Oregon Natl Primate Res Ctr, Div Diabet Obes & Metab, Beaverton, OR 97006 USA

[8] Penn State Univ, Coll Med, Hershey, PA 17033 USA

来源：

CELL METABOLISM | 2014年 / 20卷 / 05期

关键词：

AMINO-ACID CATABOLISM; BRANCHED-CHAIN; POTENTIAL ROLE; GLUCOSE; METABOLISM; LEUCINE; PLASMA; RESISTANCE; OBESE; IDENTIFICATION;

D O I：

10.1016/j.cmet.2014.09.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 alpha-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.

引用

页码：898 / 909

页数：12

共 38 条

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