Effect Of A Novel PPARγ Modulator GVS-12 On Insulin Resistance

Objective:To explore the role of the novel PPARγmodulator GVS-12 in improving insulin resistance（IR）and explore possible mechanisms of action.Methods:HepG2 cell experiments:（1）Screening for insulin concentration and incubation time that induce IR in HepG2 cells;（2）The effect of GVS-12 on the activity of HepG2 cells was observed by MTT assay;（3）Glucose consumption experiment was performed to evaluate the effect of GVS compounds on IR of HepG2 cells;（4）Western blot analysis was used to clarify the effect of GVS-12on PPARγ/AMPK/SOCS3 signaling pathways.SD rat experiments:（1）High-sugar and high-fat diet induced a rat model of IR in vivo;（2）To observe the effect of GVS-12 intervention on IR and dyslipidemia in IR rats;（3）Western blot analysis was performed to reveal the effect of GVS-12 on PPARγ-related SOCS3 and AMPK signaling pathways in rat liver tissue.Results:Effect of GVS-12 on insulin-induced IR in HepG2 cells:（1）Insulin concentration(1×10^-7mM)and incubation time（48 h）that induced IR in HepG2 cells were successfully screened.（2）GVS-12 could significantly improve IR of HepG2 cell.（3）GVS-12 could up-regulate insulin-induced decrease of PPARγand AMPK phosphorylation and inhibit the increase of SOCS3 protein expression in HepG2cells.Effect of GVS-12 on IR rats induced by high glucose and high fat diet:（1）GVS-12 could reduce HOMA-IR,serum TG and TC levels,and increase HDL-C content in rats with high glucose and high fat diet;（2）GVS-12 could up-regulate PPARγand AMPK phosphorylation and down-regulate SOCS3protein expressionin liver tissue of IR rat.Conclusions:GVS-12 can improve IR in HepG2 cells and rats,and its mechanism may be related to the regulation of hepatocyte PPARγ/AMPK/SOCS3 signaling pathway.GVS-12 has the potential to prevent and treat IR-related diseases such as T2DM and cardiovascular.