TR4 and PPARγ activities are differentially modulated by pyriproxyfen

Abstract

The 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.

Fenoxycarb promotes adipogenesis in 3T3‐L1 preadipocytes

“…Previously, we found that pyriproxyfen increased the activity of not only PPARγ but TR4 as well, at different concentrations (Choi et al . ). However, fenoxycarb did not significantly affect TR4 transcriptional activity, suggesting that fenoxycarb may facilitate lipid accumulation in adipocytes by specifically modulating PPARγ activity.…”

“…; Choi et al . ). Interestingly, these receptors play important roles in lipid and glucose metabolism.…”

Pyriproxyfen inhibits the suppressive effect of inflammatory signal on TR4 activity

“…We recently showed that PYR, a JH analog, can stimulate TR4 activity (Choi et al ). Thus, we tested whether PYR can inhibit the negative effect of TNFα on TR4 activity.…”

“…Plasmids pcDNA3‐TR4, pcDNA3‐p65, pCMX‐c‐Rel, pSG‐p50, pSG5‐PPARγ, pCMX‐RXRα, pGEX3, pGEX3‐TR4‐Full, pGEX3‐TR4‐N, pGEX3‐TR4‐ΔC, pGEX3‐TR4‐LBD, pGL3‐cDR1‐Luc, pGL3‐FATP1‐DR1‐Luc, pGL3‐PPRE‐Luc and pGL3‐NFRE‐Luc were described previously (Shyr et al ; Choi et al ; Choi et al ). TNFα and rosiglitazone were purchased from Sigma Aldrich (St. Louis, MO, USA).…”

“…Recent studies showed that 20‐hydroxyecdysone reduces diet‐induced obesity and hyperglycemia in mice (Kizelsztein et al ). In addition, we reported that Pyriproxyfen (PYR), a JH analog, enhances activity of testicular orphan nuclear receptor 4 (TR4) or peroxisome proliferator activated receptor γ (PPARγ), key transcription factors for mammalian energy homeostasis, depending on its availability, which results in increased lipid accumulation in 3 T3‐L1 adipocytes (Choi et al ). Thus, these studies indicate functional cross‐talk of hormonal signaling between insects and mammals (King‐Jones & Thummel ; Steyn et al ), implicating potential roles of insect hormones in public health.…”