Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism

Cell Metab. 2014 Nov 4;20(5):898-909. doi: 10.1016/j.cmet.2014.09.003. Epub 2014 Oct 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / metabolism
  • Amino Acids, Branched-Chain / blood*
  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Brain / metabolism*
  • Caenorhabditis elegans
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat / adverse effects
  • Hyperglycemia / blood
  • Hyperglycemia / metabolism
  • Insulin / metabolism*
  • Liver / metabolism*
  • Male
  • Mice
  • Obesity / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction

Substances

  • Amino Acids, Branched-Chain
  • Insulin
  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)