Peroxisome proliferator-activated receptor-γ coactivator-1 and insulin resistance:: acute effect of fatty acids

Aims/hypothesis: 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. Materials and 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 similar to 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 similar to 1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to similar to 53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to similar to 61, 77 and similar to 52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8- fold (all p < 0.05). Conclusions/interpretation: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.