Down regulation of peroxisome proliferator-activated receptorγ expression by inflammatory cytokines and its reversal by thiazolidinediones

Aims/hypothesis. Previous studies show that inflammatory cytokines play a part in the development of insulin resistance. Thiazolidinediones were developed as insulin-sensitizing drugs and are ligands for the peroxisome proliferator-activated receptory (PPAR gamma). We hypothesized that the anti-diabetic mechanism of thiazolidinediones depends on the quantity of PPAR gamma in the insulin resistant state in which inflammatory cytokines play a part. Methods. We isolated rat PPAR gamma 1 and gamma 2 cDNAs and examined effects of various cytokines and thiazolidinediones on PPAR gamma mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6 and leukaemia inhibitory factor decreased PPAR gamma mRNA expression. In addition, hydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetate also decreased the expression of PPAR gamma. The suppression of PPAR gamma mRNA expression caused by 10 nmol/l of TNF-alpha. was reversed 60 % and 55 % by treatment with 10(-4) mol/l of troglitazone and 10(-4) mol/l of pioglitazone, respectively. The suppression of glucose transporter 4 mRNA expression caused by TNF-alpha was also reversed by thiazolidinediones. Associated with the change of PPAR gamma mRNA expression, troglitazone improved glucose uptake suppressed by TNF-alpha. Conclusion/interpretation. Our study suggests that inflammatory cytokines could be factors that regulate PPAR gamma expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PPAR gamma mRNA expression may contribute to the anti-diabetic mechanism of thiazolidinediones.