Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle

J Biol Chem. 2002 Dec 27;277(52):50230-6. doi: 10.1074/jbc.M200958200. Epub 2002 Nov 14.

Abstract

Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Diglycerides / metabolism
  • Fat Emulsions, Intravenous / pharmacology*
  • Fatty Acids, Nonesterified / blood
  • Fatty Acids, Nonesterified / physiology
  • Insulin / pharmacology
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Kinetics
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Rats
  • Rats, Wistar

Substances

  • Diglycerides
  • Fat Emulsions, Intravenous
  • Fatty Acids, Nonesterified
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Phosphoproteins
  • Phosphotyrosine
  • Phosphatidylinositol 3-Kinases