Elevated free fatty acids attenuate the insulin-induced suppression of PDK4 gene expression in human skeletal muscle: potential role of intramuscular long-chain acyl-coenzyme A

J Clin Endocrinol Metab. 2007 Oct;92(10):3967-72. doi: 10.1210/jc.2007-1104. Epub 2007 Jul 24.

Abstract

Aim: We investigated the effect of elevated plasma free fatty acid and insulin concentrations on PDK4 mRNA transcript and protein content and long-chain acyl-coenzyme A accumulation in human skeletal muscle.

Methods: On two occasions, 10 healthy men underwent hyperinsulinemic-euglycemic clamps for 6 h with (LIPID) and without (CON) iv Intralipid (20% at 90 ml/h) plus heparin (200 U prime + 600 U/h) infusion.

Results: Glucose disposal was approximately 50% lower at the end of the clamp in the LIPID compared with the CON trial (37.8 +/- 4.4 and 79.6 +/- 4.0 micromol/kg lean mass.min, respectively; P < 0.01). In the LIPID trial, muscle long-chain acyl-coenzyme A concentration increased after 6 h, but not 3 h of lipid infusion (P < 0.01). Muscle PDK4 mRNA, but not protein, was down-regulated by 2-fold within 3 h in both clamps and decreased further (6-fold; P < 0.01) at 6 h in the CON but not the LIPID clamp. The lipid-induced attenuation in the suppression of PDK4 gene expression was not dependent on the activation of the Akt/FOXO3 pathway.

Conclusion: Accumulation of im lipids plays a more important role than impaired activation of Akt-mediated pathways in the regulation of muscle PDK4 gene expression in lipid-induced acute insulin-resistant states.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcarnitine / metabolism
  • Acyl Coenzyme A / metabolism*
  • Adult
  • Carbohydrate Metabolism / drug effects
  • Carbohydrate Metabolism / physiology
  • Fat Emulsions, Intravenous / pharmacology
  • Fatty Acids / blood*
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Glucose Clamp Technique
  • Humans
  • Hyperinsulinism / physiopathology
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood*
  • Insulin / administration & dosage
  • Insulin / blood*
  • Insulin Resistance / physiology
  • Male
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology*
  • Oxidation-Reduction / drug effects
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Acyl Coenzyme A
  • FOXO3 protein, human
  • Fat Emulsions, Intravenous
  • Fatty Acids
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • Hypoglycemic Agents
  • Insulin
  • PDK4 protein, human
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Pyruvate Dehydrogenase Complex
  • RNA, Messenger
  • Acetylcarnitine
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt