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

Aims/hypothesis. Previous studies show that inflammatory cytokines play a p art in the development of insulin resistance. Thiazolidinediones were devel oped as insulin-sensitizing drugs and are ligands for the peroxisome prolif erator-activated receptory (PPAR gamma). We hypothesized that the anti-diab etic 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 effect s of various cytokines and thiazolidinediones on PPAR gamma mRNA expression in rat mature adipocytes. Results. Various inflammatory cytokines, such as tumour necrosis factor-alp ha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6 and leuka emia inhibitory factor decreased PPAR gamma mRNA expression. In addition, h ydrogen peroxide, lysophosphatidylcholine or phorbol 12-myristate 13-acetat e also decreased the expression of PPAR gamma. The suppression of PPAR gamm a mRNA expression caused by 10 nmol/l of TNF-alpha. was reversed 60 % and 5 5 % by treatment with 10(-4) mol/l of troglitazone and 10(-4) mol/l of piog litazone, respectively. The suppression of glucose transporter 4 mRNA expre ssion caused by TNF-alpha was also reversed by thiazolidinediones. Associat ed with the change of PPAR gamma mRNA expression, troglitazone improved glu cose uptake suppressed by TNF-alpha. Conclusion/interpretation. Our study suggests that inflammatory cytokines c ould be factors that regulate PPAR gamma expression for possible modulation of insulin resistance. In addition, we speculate that the regulation of PP AR gamma mRNA expression may contribute to the anti-diabetic mechanism of t hiazolidinediones.