Brain insulin lowers circulating bcaa levels by inducing hepatic bcaa catabolism

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

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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.

Original languageEnglish
Pages (from-to)898-909
Number of pages12
JournalCell Metabolism
Volume20
Issue number5
DOIs
StatePublished - Nov 4 2014

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