Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Shin, AC; Fasshauer, M; Filatova, N; Grundell, LA; Zielinski, E; Zhou, J-Y; Scherer, T; Lindtner, C; White, PJ; Lapworth, AL; Ilkayeva, O; Knippschild, U; Wolf, AM; Scheja, L; Grove, KL; Smith, RD; Qian, W-J; Lynch, CJ; Newgard, CB; Buettner, C

Published Date

  • November 4, 2014

Published In

Volume / Issue

  • 20 / 5

Start / End Page

  • 898 - 909

PubMed ID

  • 25307860

Pubmed Central ID

  • PMC4254305

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2014.09.003


  • eng

Conference Location

  • United States