Concentration-dependent stimulatory and inhibitory effect of troglitazone on insulin-induced fatty acid synthase expression and protein kinase B activity in 3T3-L1 adipocytes

In order to study the effect of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone on the insulin-induced expression of fatty acid synthase (FAS) in adipocytes, we generated a 3T3-L1 cell line stably expressing a FAS reporter gene construct. In this cell line, a low concentration of troglitazone (250 nM) increased the effect of insulin on the FAS promoter activity and the expression of FAS protein about 1.5- to 2-fold. Since the effect of insulin on the expression of FAS is believed to be mediated by activation of protein kinase B (PKB), we investigated the effect of troglitazone on the regulation of PKB. Troglitazone (250 nM) increased the maximal effect of insulin on PKB activity about twofold without significantly affecting its EC50 (1.4+/-0.5 nM vs. 2.2+/-0.6 nM in controls). Higher concentrations of troglitazone (>1 muM) inhibited both insulin-stimulated PKB activity and expression of FAS. In summary, our data indicate a dual effect of troglitazone on the insulin-induced FAS gene expression in 3T3-L1 cells. The therapeutic, stimulatory effect is produced by low concentrations of troglitazone (250 nM), and is presumably mediated by enhanced activation of PKB.