The Mechanisms Of Liver X Receptor On Improving Insulin Resistance In Adipose Tissue

Objective: Liver x receptors are members of nuclear receptor family and haveimportant roles in metabolic pathways, including bile acid synthesis, glucose and lipidhomeostasis. In the present study, we investigated glucose metabolism in adipose tissueand3T3-L1adipocytes in both basal and insulin resistant status and further elucidated themolecular mechanisms of TO901317, one of LXR agonists, on the improvement of insulinresistance.Methods:(1) Male db/db mice and C57BL/6mice were enrolled and divided intofour groups at random, db/db Con, db/db TO, C57Con and C57TO with nine mice ineach group. The groups of db/db TO and C57TO were intraperitoneally (i.p.) givenTO901317solubilized in DMSO at a dose of30mg/kg/day for two weeks, and the othertwo groups were given the same volume of DMSO as control. The weight, fasting bloodglucose (FBG), fasting insulin (Fins), free fatty acid (FFA) of all groups of mice wereestimated and the insulin tolerance test(ITT) was performed after the last TO901317treatment.(2) At study completion, adipose tissue samples were collected and total RNAswere isolated. We examined the mRNA expressions of hexokinase (HK), glucosetransporter4(GLUT4) and the expressions of Akt in C57mice and db/db mice. In3T3-L1adipocytes, we utilized palmitate (PA) to induce insulin resistance with the evaluation ofthe phosphorylation of Akt (P-Akt). And glucose uptake capacity was observed after thetreatment of PA in3T3-L1cells with or without TO901317. We also examined the transcriptions of HK, GLUT4and the expressions of P-Akt in3T3-L1adipocytes underinsulin resistant status with or without the treatment of TO901317.(3) We further exploredthe expression of P-JNK in db/db mice, C57mice and3T3-L1adipocytes in insulinresistant state with or without TO901317treatment.Results:(1) Compared with C57mice, db/db mice had higher index in weight, bloodglucose area under curve (AUC), FFA, HOMA-IS (P＜0.05) and lower index in ISI (P＜0.05). The AUC were decreased and HOMA-IS and ISI increased respectively in db/dbTO mice, compared with db/db Con mice, whereas no statistically significant differencesin weight and FFA were found. Compared with C57Con mice, no significant changes ofweight, AUC, FFA, HOMA-IS, ISI were obtained in C57TO mice.(2) In animal models,the mRNA expressions of HK, GLUT4were significantly up-regulated in treated db/dbmice (P＜0.05), but not altered in C57mice. The treatment of TO901317increasedphosphorylation of Akt with total Akt unchanged in db/db mice while no significantchanges were found in C57mice. In3T3-L1cells, the expressions of P-Akt weredown-regulated in palmitate-induced insulin resistance. After the use of TO901317,glucose uptake was dramatically augmented in insulin resistant3T3-L1cells (P＜0.05).The treatment of TO901317remarkably increased the transcriptions of HK and GLUT4inPA-treated3T3-L1adipocytes (P＜0.05). But TO901317alone only increased thetranscription of GLUT4(P＜0.05), whereas the expressions of HK remained unchanged.Compared with the use of PA, the expressions of P-Akt were also increased in combinedapplication of TO901317and PA.(3) The treatment of TO901317suppressed thephosphorylation of JNK with total JNK unchanged in db/db mice while no significantchanges were found in C57mice. Very similar trends were obtained in3T3-L1adipocytestreated with PA and TO901317.Conclusions:(1) The activation of LXR can improve glucose metabolism andenhance insulin sensitivity in insulin resistant status. But no significant results wereobtained in normal circumstances.(2) The effects of LXR in glucose metabolism had acloser relationship with the increase expressions of HK, GLUT4and the phosphorylationof Akt.(3) LXR could increase the phosphorylation of Akt through suppressing thephosphorylation of JNK, thus improving insulin resistance.