TR4 and PPARγ activities are differentially modulated by pyriproxyfen

Abstract

AbstractThe TR4 orphan receptor (TR4) has been suggested to mediate the effect of pyriproxyfen (PYR), a juvenile hormone (JH) analog, on lipid metabolism in adipocytes. PYR was shown to stimulate activity of TR4 only at a relatively low concentration. Thus, the effect of PYR on the adipocyte biology at higher dosages remains unclear. Here, we demonstrate that high concentration (400 μM) of PYR is still able to promote adipogenesis of 3T3‐L1 cells. Furthermore, peroxisome proliferator‐activated receptor gamma (PPARγ) transcriptional activity is dramatically enhanced at 400 μM PYR, to which TR4 does not respond. In a gel shift assay, TR4 and PPARγ compete with each other for binding to a common binding site, direct repeat 1 (DR1), resulting in mutual reduction of both TR4 and PPARγ DNA binding. However, there is no interaction between TR4 and PPARγ, suggesting that depending on relative availability of TR4 and PPARγ during adipogenesis of 3T3‐L1 cells, TR4 or PPARγ may independently mediate the PYR effect on adipogenesis at different concentrations. Together, our data show that PYR has a lipogenic role in 3T3‐L1 adipocytes and thus, JH and its related molecules may provide a new preventive and therapeutic approach for diseases linked to lipid metabolism.