Intracerebroventricular Secreted Frizzled-protein 5 Infusion Regulates Glucose Metabolism In Diet-induced Insulin Resistance Rats And Potential Mechanism

Aim: To investigate the effect of intracerebroventricular Sfrp5 infusion on hepatic glucose homeostasis and insulin sensitivity in diet-induced insulin resisitance rats and related mechanism.Methods: SD rats were fed ad libitum with normal chow diet and high-fat diet for 12 weeks and randomly divided into:1)NCD+icv aCSF group,2)NCD+icv Sfrp5 group,3)HFD+icv aCSF group,4)HFD+icv Sfrp5 group,5)NCD+icv aCSF+iv.Saline group,6)NCD+icv aCSF+iv.Lipid group,7)NCD+icv Sfrp5+iv.Saline group,8)NCD+icv Sfrp5+iv.Lipid group,9)HFD+icv aCSF+DVC saline group,10)HFD+icv aCSF+DVC MK801 group,11)HFD+icv Sfrp5+DVC saline group,12)HFD+icv Sfrp5+DVC MK801 group,13)HFD+icv aCSF group,14)FD+icv Glibenclaim group,15)HFD+icv Sfrp5 group,16)HFD+icv Glibenclaim/Sfrp5 group,17)HFD+icv Diazoxide group.Rats were implanted with catheters in the third cerebral ventricle or dorsal vagal complex(DVC).Glucose metabolism and insulin sensetivity were by using intraperitoneal glucose tolerance tests and hyperinsulinemic-euglycemicclamp study in conscious rats.Results: Compared with normal chow diet rats,food intake,weight and temperature were significantly increased in the high-fat rats(all p <0.01).While,O2 consumption,CO2 production and RER were significantly decreased(all p<0.01).When the expression of Sfrp5 was higher,namely compared with the group of HFD+icv CSF,food intake,weight and temperature of the group of HFD+icv Sfrp5 were significantly decreased(p<0.05 or p<0.01);while,O2 consumption,CO2 production and RER were increased(all p < 0.01).The AUC of blood and insulin of the group of HFD+icv Sfrp5 were sharply reduced than the group of HFD+icv aCSF(p<0.01).When increasing the level of plasma LCFAs through lipid infusion stimulates gluconeogenisis,but the higher central expression of Sfrp5 can reverse the alteration.Central Sfrp5 infusion can increase the insulin sensitivity and improve glucose homeostasis of high-fat diet induced insulin resistance SD rats,whereas NMDA receptor blocker MK801 negated the influence of Sfrp5,DVC infusion ML801 alone didn’t have this kind impact.Glibenclamide,the K-ATP blocker,abolished the improvement when co-infusioning Sfrp5 with glibenclamide.However,ICV infusing glibenclamide alone did not have any effect on glucose homeostasis.Meanwhile,ICV infusing Diazioxide alone had the same effect with ICV infusing Sfrp5 alone.Conclusion: Central high-expression of Sfrp5 can improve the insulin resistance and hepatic glucose metabolism of the high-fat diet induced insulin resistance rats,and the mechanism related to the activation of K-ATP channel and the brain-liver axis.