Effects of BRD4 Inhibitor JQ1 and/or Endurance Exercise Intervention on Glucose and Lipid Metabolism Disorders in Insulin-resistant Mice
Objective To investigate the effect of bromine domain protein 4(BRD4)inhibitor JQ1 and/or endurance exercise on glucose and lipid metabolism disorder in insulin resistant mice,and its mechanism.Methods Sixty C57BL/6 J mice were ran-domly divided into normal diet group(Con,n=10)and high fat diet group(HFD,n=50).HFD group was fed with high-fat diet for 12 weeks to establish insulin resistance model,and then randomly divided into high-fat diet group(HFD),JQ1 group(HFD+J),endurance exercise group(HFD+E)and J Q1+endurance exercise group(HFD+JE),with 10 mice in each group.The JQ1 group received intraperitoneal injection of JQ1(10 mg/kg,6 d/week,6 weeks),and the exercise group performed treadmill exer-cise(13 m/min,60 min/d,6 d/week,6 weeks).IPGTT and IPITT tests were performed after 6 weeks of intervention.Serum T-CHO,TG,HDL-C,LDL-C and NEFA were measured by microplate method.Myocardial BRD4,GLUT4,AMPK,autophagy in-dexes P62 and LC3,as well as the expressions of ER stress index GRP78,ATF4,IRE1,eIF2α and CHOP were detected by Western blotting.Results After 12 weeks of high fat feeding,body weight,fasting blood glucose and IPGTT-AUC in HFD group were significantly increased compared with Con group.After 6 weeks of intervention,serum NEFA in HFD+J group was significantly lower than that in HFD group.Serum TG,T-CHO and NEFA were significantly decreased in HFD+E group.IPITT-AUC,serum T-CHO,LDL-C and NEFA were significantly decreased,and HDL-C was significantly increased in HFD+JE group.Compared with HFD group,the expressions of p-AMPK/AMPK and GLUT4 in HFD+JE group were signifi-cantly increased.Compared with HFD group,BRD4 expression was significantly downregulated,and LAMP1 expression was significantly upregulated in HFD+J group.In HFD+E group,the expressions of BRD4 and P62 were significantly downregu-lated,and the ratio of LC3 Ⅱ/LC3 Ⅰ was significantly upregulated.The expressions of BRD4 and P62 in HFD+JE group were significantly downregulated,and the ratios of LAMP1 and LC3 Ⅱ/LC3 Ⅰ were significantly upregulated.Compared with HFD group,the expressions of GRP78,p-IRE1/IRE1 and CHOP in HFD+J group were significantly downregulated.The expressions of GRP78,p-IRE1/IRE1,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+E group.The expressions of GRP78,p-eIF2α/eIF2α and CHOP were significantly downregulated in HFD+JE group.Conclusion JQ1 can antagonize myo-cardial BRD4 in insulin-resistant mice,improving autophagy and ERS.Yet it only contributes to a partial effect on glycolipid me-tabolism.Both endurance exercise and combined intervention can inhibit myocardial BRD4-mediated autophagy and ERS,impro-ving glucose and lipid metabolic disorder.The combination of these two interventions has a more significant effect,which may be related to BRD4 inhibition and autophagy function improvement.
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维普
