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.
OBJECTIVE
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.


CONCLUSIONS
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.
Tsintzas
Kostas
K
Centre for Integrated Systems Biology and Medicine, Institute of Clinical Research, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom. kostas.tsintzas@nottingham.ac.uk.
Chokkalingam
Kamal
K
Jewell
Kirsty
K
Norton
Luke
L
Macdonald
Ian A
IA
Constantin-Teodosiu
Dumitru
D
D000108:Acetylcarnitine / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism*; D000328:Adult; D050260:Carbohydrate Metabolism / Q000187:drug effects / Q000502:physiology; D005217:Fat Emulsions, Intravenous / Q000494:pharmacology; D005227:Fatty Acids / Q000097:blood*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D010084:Oxidation-Reduction / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000214:Acyl Coenzyme A; C499517:FOXO3 protein, human; D005217:Fat Emulsions, Intravenous; D005227:Fatty Acids; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; C000631432:PDK4 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D000108:Acetylcarnitine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt