Pyriproxyfen inhibits the suppressive effect of inflammatory signal on TR4 activity

Abstract

AbstractObesity causes a chronic inflammatory state by increasing secretion of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα), which alters signaling pathways critical for metabolic homeostasis, leading to obesity‐related metabolic disorders. Here, we demonstrate that TNFα inhibits testicular orphan nuclear receptor 4 (TR4) transcriptional activity and this TNFα inhibition of TR4 activity is reduced by treatment of Pyriproxyfen (PYR), a juvenile hormone (JH) analog. In addition, nuclear factor‐kappa B (NF‐κB), a key transcription regulator of inflammation, also suppressed TR4 transactivation by physical interaction with TR4, reducing TR4 binding affinity for TR4 response elements located in its target gene promoters. Consistently, NF‐κB‐suppressed TR4 activity was partially restored by PYR treatment. Furthermore, TNFα inhibited mRNA levels of TR4 target genes such as, FATP1 and PC with reduction of lipid accumulation in 3 T3‐L1 adipocytes while PYR suppressed TNFα inhibition of TR4 target gene expression, resulting in recovery of lipid accumulation of adipocytes, suggesting that PYR enhances lipid homeostasis disturbed by inflammatory signaling and this PYR effect could be achieved in part by stimulating TR4 transcriptional activity. Together, our data show that PYR regulates inflammatory signaling in adipocytes and thus, small molecules based on insect hormones could be an alternative approach to control obesity‐related metabolic disorders.