The Discovery Of A Novel PPARγ Agonist And Establishment Of Screening Model For LGR4 Modulator

With the improvement of quality of life and changing of lifestyle,many people increase food intake of high sugar and lipid.At the same time,people have no exercise and have a sedentary lifestyle.Therefore,energy metabolism of human body is unbalanced,finally obesity and diabetes happen.All over the world,the diabetic continues to increase,China has become the first of diabetic,the diabetic complication badly threaten health.On the one hard,our aim is to find a new safe and effective PPARγ partial agonist for the treatment of diabetes candidates.On the other hard,establishment of screening model for LGR4 modulator can provide a tool that research on LGR4 in deeper,it can provide a new strategy of obesity and metabolic disease.In post-translational modifications regulate PPARγ research,phosphorylation of PPARγ by cyclin-dependent kinase 5(CDK5)at serine 273 can induce insulin resistance.Blocking the CDK5-mediated PPARγ phosphorylation can improve insulin sensitivity and not affect its other functions,such as adipogenic capacity.It can avoid side effects of PPARγ full agonists,such as fluid retention,weight gain,increase white adipose,increased appetite,and will accomplish partial activation.On the other hand,we apply bioluminescence resonance energy transfer(BRET)and test Wnt signal methods to establish screening model.In our study,we obtain the compound VSP-51-2 that a novel partial agonist.VSP-51-2(20 mg/kg)can improve insulin sensitivity and control blood glucose in ob/ob mice.VSP-51-2 increases to 50 mg/kg can improve insulin sensitivity and control blood glucose,and can avoid incremental food intake,weight gain,heart and brain ratio rised in DIO mice.And VSP-51-2 can selective activate PPARγ downstream gene,in liver and adipose tissue of DIO mice.Expression of PPARγ full agonist gene had no increase in adipose tissue of DIO mice.On the other hard,We successfully constructed fusion expression plasmids of Rluc-LGR4-LRR8,RSPO1-EYFP,Rluc-EYFP for BRET,and ensured stable Wnt signal to screen.