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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

Centre for Integrated Systems Biology and Medicine, Institute of Clinical Research, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom

Address all correspondence and requests for reprints to: Kostas Tsintzas, Centre for Integrated Systems Biology and Medicine, Institute of Clinical Research, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom. E-mail: kostas.tsintzas{at}nottingham.ac.uk.

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 µmol/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.

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