Peroxisome proliferator-activated receptor-gamma coactivator-1 and insulin resistance: acute effect of fatty acids.
OBJECTIVE
Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans.


METHODS
Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic-euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR.


RESULTS
Lipid infusion resulted in a approximately 2.7-fold increase in plasma NEFA levels and a 31+/-6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a approximately 1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to approximately 53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to approximately 61, 77 and approximately 52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05).


CONCLUSIONS
Acute elevation of plasma NEFA levels, leading to muscular fat accumulation and insulin resistance, downregulates PPARGC1A, PPARGC1B and PPARA expression, suggesting that the decrease in PPARGC1 expression observed in the (pre)diabetic state may be the result, rather than the cause of lipid-induced insulin resistance.
Hoeks
J
J
Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. j.hoeks@hb.unimaas.nl
Hesselink
M K C
MK
Russell
A P
AP
Mensink
M
M
Saris
W H M
WH
Mensink
R P
RP
Schrauwen
P
P
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002352:Carrier Proteins / Q000235:genetics*; D004655:Emulsions; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D047493:PPAR alpha / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D001786:Blood Glucose; D002352:Carrier Proteins; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D006360:Heat-Shock Proteins; D047493:PPAR alpha; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1