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  • This study has discovered an interesting cross talk between

    2019-07-24

    This study has discovered an interesting cross-talk between TZD and TRPV1 and shows a direct activating effect of TRPV1 by TZD derivatives. Recently, PPARγ agonists have been shown to cause browning of white adipocytes [5,20,38,39] by stabilizing PPARγ and PRDM-16, a gene responsible for this molecular switch. Since TRPV1 activation caused browning of white adipose tissue, TZDs may trigger browning program in 3T3-L1 Cytochalasin D TRPV1 activation. The ability of Trog and Rosi to activate TRPV1 as well as enhance PPARγ rises an important question – whether these compounds mediate this effect directly or via PPARγ. However, in control HEK293 cells that lack TRPV1 endogenously, Trog failed to stimulate a Ca2+ influx. These data suggest that Trog presumably mediates its effect directly on TRPV1 and not via PPARγ activation. Also, the induction of Ca2+ influx by Trog was spontaneous in 3T3-L1TRPV1 cells as there was no time delay between the application of Trog and the influx of Ca2+. However, the effect of Rosi was lower than Trog. One reason for this could be the difference in the structure of these compounds. Further in vitro studies and molecular docking analyses are required to address this. Nevertheless, our data demonstrate that TRPV1 is activated by TZD, which will have a clinical significance since TZDs are used as insulin sensitizing agents as they activate PPARγ. Published literature suggests that activation of TRPV1 also improves insulin sensitivity and promotes better glucose handling in rodents. Therefore, it is reasonable to speculate a permissive role of TRPV1 activation in the insulin-sensitizing effects of TZDs. However, whether TRPV1 activation modulates the transcriptional activity of PPARγ still remains to be determined. Nonetheless, capsaicin or Trog treatment not only enhanced the expression of PPARγ in 3T3-L1TRPV1 cells but also decreased its acetylated levels in 3T3-L1TRPV1 cells. Further, this effect of capsaicin or Trog is reversed by TRPV1 inhibition. Moreover, inhibition of SiRT-1 by EX527 prevents the deacetylation of PPARγ by capsaicin. These observations raise important questions on the ability of TRPV1 activation on the transcriptional activity of PPARγ. Future studies are warranted to clarify this. This study presents an interesting observation that TRPV1 expression and activity were suppressed in differentiated 3T3-L1TRPV1 cells. We observed a progressive loss of TRPV1 in these cells as differentiation progressed. Also, Trog failed to enhance TRPV1 and thermogenic BMP8b and SiRT-1 in differentiated 3T3-L1 cells. We performed experiments to overexpress TRPV1 in these cells but the transfection efficiency was very low. These data indicate that accumulation of fat (lipid) during the differentiation process suppresses TRPV1. This is consistent with a previous report, which suggests the suppressive effect of differentiation on TRPV1 in 3T3-L1 cells [28]. Further, the suppression of BMP8b and SiRT-1 in the differentiated cells also suggests that lipid accumulation has a profound inhibitory effect on thermogenic genes. However, the molecular mechanisms by which lipid accumulation downregulates TRPV1 and other thermogenic genes still remain to be determined. Collectively, this research sheds new light on the activating role of TZD on TRPV1 and in the regulation of adipogenic and thermogenic protein expression in 3T3-L1TRPV1 cells. Based on this, it is reasonable to speculate the existence of an unexplored direct or an indirect crosstalk between TRPV1 and PPARγ, which could be important for the browning of WAT. If TZD can activate TRPV1 to enhance the browning of WAT, will TRPV1 play a direct role in insulin sensitization mechanisms of TZD? This is significant since capsaicin has been shown previously to enhance insulin sensitivity and improve glucose tolerance [[40], [41], [42], [43], [44], [45]] in mice. Until now, such a beneficial effect of TRPV1 activation is often considered as secondary to its anti-obesity action. The direct effect of TZD to activate TRPV1 and enhance PPARγ deacetylation via TRPV1-dependent pathway indicates a more direct role of TRPV1 activation in glucose homeostasis. Further, in vivo studies are required to decipher this and evaluate the role of TRPV1 in the beneficial and adverse effects of TZD. Nevertheless, the data presented here demonstrate the potential of TRPV1 as an attractive target for ameliorating metabolic dysfunctions.