Induction of plasminogen activator inhibitor‐1 (PAI‐1) gene expression in adipocytes by thiazolidinediones

We studied the effect of thiazolidinediones (TZDs) on the regulation of plasminogen activator inhibitor 1 (PAI‐1) gene expression during 3T3‐L1 adipocyte differentiation. Treatment of the cells with pioglitazone and insulin shortened the time for differentiation from 9 d to 3 d, which resulted in a dramatic increase in PAI‐1 mRNA as well as PAI‐1 antigen secreted into the culture medium. Insulin or pioglitazone alone had relatively little effect on the rate of cell differentiation and did not alter PAI‐1 mRNA levels. A number of other TZDs (e.g., troglitazone, ciglitazone) also induced PAI‐1 gene expression in the presence of insulin, and the magnitude of induction was approximately proportional to the ability of these molecules to activate the nuclear receptor, peroxisome proliferator‐activated receptor‐γ. We also studied the mechanism of induction of PAI‐1 mRNA by pioglitazone/insulin. Although the half‐life of adipocyte PAI‐1 mRNA was not changed upon treatment with pioglitazone/insulin, this treatment induced PAI‐1 promoter activity 10‐fold. These results indicate that PAI‐1 mRNA and protein are up‐regulated by TZDs in an insulin‐dependent manner and that these effects result from an increase in the rate of transcription of the PAI‐1 gene. The increase in PAI‐1 occurs in parallel with the induction of adipogenesis, which suggests that the two processes are related.