Troglitazone reduces the expression of PPARgamma while stimulating that of PPARalpha in mononuclear cells in obese subjects

We have recently demonstrated that troglitazone exerts an anti-inflammatory effect in the insulin resistant obese in vivo in parallel with its insulin-sensitizing effect. Because these effects are thought to be mediated through peroxisome proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma), we have now examined the possibility that troglitazone may modulate the expression of PPARalpha and PPARgamma. Seven obese hyperinsulinemic subjects were administered 400 mg troglitazone daily for 4 weeks. Fasting blood samples were obtained before and during troglitazone therapy at 1, 2, and 4 weeks. Fasting insulin concentrations fell at week 1 and persisted at lower levels till 4 weeks. PPARgamma expression fell significantly at week 1 and fell further at weeks 2 and 4. In contrast, PPARalpha expression increased significantly at week 2 and further at week 4. 9- and 13-hydroxyoctadecanoic acid, products of linoleic acid peroxidation and agonists of PPARgamma, decreased during troglitazone therapy. We conclude that troglitazone, an agonist for both PPARalpha and PPARgamma, has significant but dramatically opposite effects on PPARalpha and PPARgamma. These effects may be relevant to its insulin sensitizing and anti-inflammatory effects.