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

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 mu mol/ 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.