Peroxisome Proliferator-Activated Receptor γ activation enhances insulin-stimulated glucose disposal by reducing ped/pea-15 expression in skeletal muscle cells. Evidence for involvement of Activator Protein-1.

The gene network responsible for inflammation-induced insulin resistance remains enigmatic. In this study, we show that, in L6 cells, rosiglitazone as well as pioglitazone-dependent activation of PPARγ represses transcription of ped/pea-15 gene, whose increased activity impairs glucose tolerance in mice and in humans. Rosiglitazone enhanced insulin-induced glucose uptake in L6 cells expressing the endogenous ped/pea-15 gene but not in cells expressing ped/pea-15 under the control of an exogenous promoter. The ability of PPARγ to affect ped/pea-15 expression was also lost in cells and in C57BL/6J transgenic mice expressing ped/pea-15 under the control of an exogenous promoter, suggesting that ped/pea-15 repression may contribute to rosiglitazone action on glucose disposal. Indeed, high-fat diet mice showed insulin resistance and increased ped/pea-15 levels, while these effects were reduced by rosiglitazone treatment. Both supershift and ChIP assays revealed the presence of the AP-1 component c-JUN at PED/PEA-15 promoter upon TPA stimulation of the cells. In these experiments, rosiglitazone treatment reduced c-JUN presence at PED/PEA-15 promoter. This effect was not associated with a decrease in c-JUN expression. In addition, c-jun silencing in L6 cells lowered ped/pea-15 expression and caused non-responsiveness to rosiglitazone, while c-jun overexpression enhanced the binding to ped/pea-15 promoter and blocked rosiglitazone effect. These results indicate that PPARγ regulates ped/pea-15 transcription by inhibiting c-jun binding at ped/pea-15 promoter. Thus, ped/pea-15 is downstream major PPARγ-regulated inflammatory networks. Repression of ped/pea-15 transcription might contribute to the PPARγ regulation of muscle sensitivity to insulin.