Pyriproxyfen enhances the Immunoglobulin G immune response in mice

Park²,

2017

Obesity 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.

Section: Discussionmentioning

confidence: 99%

Pyriproxyfen inhibits the suppressive effect of inflammatory signal on TR4 activity

Park²,

2017

“…Accumulating evidence has shown that insect hormones affect various aspects of mammalian physiology. Because of structural or/and functional similarities of ecdysteroids and JHs with mammalian hormones such as steroids, derivatives of vitamins A and D3 and isoprenoids, several studies have suggested that these hormones may function as physiological modulators in mammals in part through transactivation of mammalian nuclear receptors Kizelsztein et al 2009;Sharmin et al 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Epidemiological studies showed that chronic exposure to pesticides has a close relationship with a higher risk of various cancers (Alavanja et al 2004). The effect of PYR on mammalian physiology has been reported in several studies (Matsunaga et al 1995;Yoshino et al 1995Yoshino et al , 1996Sharmin et al 2013). Matsunaga et al (1995) reported that PYR and its derivatives are rapidly excreted and only trace amount of their residues are detected in blood, kidney and liver.…”

Section: Introductionmentioning

confidence: 99%

TR4 and PPARγ activities are differentially modulated by pyriproxyfen

Park

2014

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.

“…; Sharmin et al . ). Because of the profound structural and/or functional similarities of these hormones between insects and mammals, many studies have demonstrated physiological effects of 20E and JH in mammals.…”

Section: Introductionmentioning

confidence: 97%

“…In mammals, lipophilic hormones, such as steroids, derivatives of vitamins A and D3 and isoprenoids, play important roles in reproduction, development and metabolism. These molecules act by binding to cognate receptors, which regulate transcription of a variety of genes (Wurtz et al 2000;Kizelsztein et al 2009;Sharmin et al 2013). Because of the profound structural and/or functional similarities of these hormones between insects and mammals, many studies have demonstrated physiological effects of 20E and JH in mammals.…”

Section: Introductionmentioning

confidence: 99%

Fenoxycarb promotes adipogenesis in 3T3‐L1 preadipocytes

Lim

et al. 2016

Lipophilic insect hormones and their analogs affect mammalian physiology by regulating the expression of metabolic genes. Therefore, we determined the effect of fenoxycarb, a juvenile hormone analog, on lipid metabolism in adipocytes. Here, we demonstrated that fenoxycarb dose‐dependently promoted lipid accumulation in 3T3‐L1 adipocytes during adipocyte differentiation and that its lipogenic effect was comparable to that of rosiglitazone, a well‐known ligand for peroxisome proliferator‐activated receptor gamma (PPARγ). Furthermore, fenoxycarb stimulated PPARγ activity without affecting other nuclear receptors, such as liver X receptor (LXR), farnesoid X‐activated receptor (FXR) and Nur77. In addition, fenoxycarb treatment increased the expression of PPARγ and fatty acid transporter protein 1 (FATP1) in 3T3‐L1 adipocytes, suggesting that fenoxycarb may facilitate adipocyte differentiation by enhancing PPARγ signaling, the master regulator of adipogenesis. Together, our results suggest that fenoxycarb promoted lipid accumulation in adipocytes, in part, by stimulating PPARγ.