The expression of the p85α subunit of phosphatidylinositol 3-Kinase is induced by activation of the peroxisome proliferator-activated receptor γ in human adipocytes

Aims/hypothesis. Thiazolidinediones are new oral antidiabetic drugs that activate the nuclear receptor PPAR gamma. Our aim was to identify potential target genes of PPAR gamma in the human adipocyte in order to clarify how thiazolidinediones improve insulin sensitivity. Methods.. The effect of BRL 49653 (Rosiglitazone) on the mRNA expression of insulin receptor, insulin receptor substrate-1, p85 alpha, p110 alpha and p110 beta subunits of phosphatidylinositol 3-kinase, Glut 4 and hormone sensitive lipase was examined in isolated adipocytes, Target mRNA levels were determined by RT-competitive PCR. Results. The BRL 49653 (1 mu mol/l) increased the mRNA concentrations of p85 alpha PI-3 K (264 +/- 46 vs 161 +/- 31 amol/mug total RNA, p = 0.003) whithout: affecting the expression of the other mRNAs of interest. This effect was dose-dependent (K-0.5 = 5 nmol/l) and was reproduced by a specific activator of RXR, indicating that it was probably mediated by the PPAR gamma /RXR heterodimer. The BRL 49653 also increased the amount of p85 alpha PI-3K( protein in adipose tissue explants (71 +/- 19%). In addition, BRL 49653 produced a more than twofold increase in insulin stimulation of phosphatidylinositol 3-kinase activity and significantly enhanced the antilipolytic action of insulin. Conclusion/interpretation. This work demonstrates that the gene Of p85 alpha PI-3K is probably a target of PPAR gamma and that thiazolidinediones san improve insulin action in normal human adipocytes. Although the precise mechanism of action of BRL. 49653 on PI3-Kinase activity is not completely clear, those findings improve our understanding of the insulin-sensitizing effects of the thiazolidinediones, possible drugs far the treatment of Type II (non-insulin-dependent) diabetes mellitus.