Inhibition of adipose differentiation by phosphatidylinositol 3-kinase inhibitors.

Phosphatidylinositol (PI) 3-kinase plays an important role in various cellular signaling mechanisms in several cell systems. The role of PI 3-kinase in adipose differentiation was investigated. For this purpose, we examined the effect of specific inhibitors of PI 3-kinase on the differentiation of two adipogenic cell lines, 1246 and 3T3-L1. The results show that two structurally different inhibitors of PI 3-kinase, i.e., LY294002 and wortmannin, blocked adipose differentiation in a time and dose-dependent fashion. The results from time- course studies indicated that PI 3-kinase activity is most important in the early phase (day 4 to day 6) of the differentiation program. The effect of PI 3-kinase inhibitor on the expression of the peroxisome proliferator-activated receptor (PPAR) gamma, a master regulator in adipogenesis induced during the differentiation process, was also examined. LY294002 significantly inhibited the induction of PPARgamma mRNA expression. During the initiation phase of adipogenesis (day 4 to day 6), the expression of PPARgamma was induced and LY294002 blocked the increase of expression of PPARgamma mRNA. The inhibition of expression of PPARgamma may provide a molecular mechanism for the action of PI 3-kinase inhibitors on adipose differentiation.