Intracerebroventricular Sfrp5 Infusion Regulates The Hepatic VLDL-TG Secretion In Rats With Hypothalamic Inflammation Induced By High Fat Diet And Mechanisms

PART 1 THE EFFECT OF HIGH-FAT-DIET ON HYPOTHALAMIC EXPRESSION OF SFRP5 AND WNT LIGANDS IN RATSAim : To detect the hypothalamic expression of Sfrp5 and Wnt ligands in rats fed with normal diet and high fat diet respectively.Methods: SD rats fed with normal chow diet and high fat diet for 16 weeks respectively were chosen and then randomly divided into 2 goups :normal chow diet group,NCD and high fat diet,HFD.The expression of Wnt5 a and TNF? in hypothalamus were detected by Real time PCR.Meanwhile,western bloting was used to evaluate the expression of sfrp5,JNK and p-JNK.Results: The hypothalamic expression of wnt5 a m RNA was raised significantly in HFD group compared to NCD group(p<0.05),the expression of TNF? m RNA were increased significantly in HFD group compared to NCD group(p<0.01).Meanwhile,the expression of wnt5 a protein and p-JNK/JNK ratio were upregulated markedly compared to controls(p<0.01,p<0.05).However,the expression of Sfrp5 protein was decreased significantly in HFD group compared to NCD group(p<0.01).Conclusion: high fat diet can result in hypothalamic inflammtion companied by decreased expression of Sfrp5.PART ? INTRACEREBROVENTRICULAR SFRP5 INFUSION REGULATES THE HEPATIC VLDL-TG SECRETION IN RATS WITH HYPOTHALAMIC INFLAMMATION INDUCED BY HIGH FAT DIET VIA JNK PATHWAYAim: To investigate the effect of intracerebroventricular Sfrp5 infusion on hepatic VLDL-TG secretion in rats of hypothalamic inflammation induced by high fat dietMethod S: SD rats were fed ad libitum with normal chow diet and high fat diet for 16 weeks respectively.Rats were implanted with single catheters in the third cerebral ventricle and randomly divided into:(ICV a CSF)+NCD,(ICV sfrp5)+NCD,(ICV a CSF)+HFD,(ICV sfrp5)+HFD,(HFD+Saline,iv),(HFD+sfrp5,iv)respectively.blood was obtained and the rate of hepatic VLDL-TG secretion was measured following tyloxapol(an inhibitor of lipoprotein lipase)injection.The expressions of JNK,p-JNK were dectected by Western blot.Results: Central Sfrp5 infusion lowerd significantly VLDL-TG secretion in(ICV sfrp5)+HFD group compared to(ICV a CSF)+HFD group(p<0.01).The change is independent of plasma FFA level.However,The hypolipidemic effect induced by ICV Sfrp5 was not observed in rat fed normal chow diet(p>0.05).Furthormore,peripheral injection of Sfrp5 can not influence hapatic VLDL-TG in rats fed high fat diet(p>0.05).The ration of p-JNK/JNK in hypothalamus in(ICV sfrp5)+HFD groups was markedly decreased compared to(ICV a CSF)+HFD groups(p<0.01).Conclusion: Central administration of Sfrp5 controls hepatic VLDL-TG secretion in rat with hypothalamic inflammation induced by high-fat-diet through inhibiting JNK pathway.PART ? INTRACEREBROVENTRICULAR SFRP5 INFUSION REGULATES THE HEPATIC VLDL-TG SECRETION IN RATS FED WITH HIGH FAT DIET VIA ACTIVATING HYPOTHALAMIC KATP SENSITIVE CHANNELSAim: To detect whether the hypolipidemic effect of central sfrp5 infusion is dependent on activation of hypothalamic KATP sensitive channels.Methrods: SD rats were fed ad libitum with normal chow diet and high fat diet for 16 weeks respectively.Rats were implanted with single catheters in the third cerebral ventricle and randomly divided into:(ICV a CSF)groups,(ICV glibenclamide)groups,(ICV sfrp5)groups,ICV(sfrp5+ glibenclamide)groups,(ICV Diazoxide)+HFD groups,(ICV a CSF)+NCD groups,(ICV Sfrp5)+NCD groups,(ICV Diazoxide)+NCD respectively.blood was obtained and the rate of hepatic VLDL-TG secretion was measured following tyloxapol(an inhibitor of lipoprotein lipase)injection.Results: central Sfrp5 infusion decrease significantly hapatic VLDL-TG secretion(p<0.01).However,the hypolipidemic effect was abolised by co-infusion of Sfrp5 and glibenclamide(KATP blocker).ICV infusion of glibenclamide alone did not modify the hepatic VLDL-TG secretion.Meanwhille,ICV infusion of Diazoxide alone markedly decreased hepatic VLDL-TG secretion in rats fed with NCD or HFD compared to controls(p<0.01).Conclusion: Activation of KATP channels is sufficient and necessary for central sfrp5 infusion to lower VLDL-TG secretion.PART ? INTRACEREBROVENTRICULAR SFRP5 INFUSION DECREASE HEPATIC VLDL-TG IN RATS WITH HYPOTHALAMIC INFLAMMATION IN DEPENDENT ON BRAIN-LIVER AXISAim: To investigate the role of brain-liver axis in hypolipidemic effect of Sfrp5 in rats with hypothalamic inflammation.Merthods: SD rats were fed ad libitum with normal chow diet and high fat diet for 16 weeks respectively.Rats were implanted with catheters into the third cerebral ventricle and dorsal vagal complex(DVC)and performed by hepatic branch vagotomy.All rats were randomly divided into ICV(a CSF)+DVC(Saline)groups,ICV(a CSF)+DVC(MK801)groups,ICV(Sfrp5)+DVC(Saline)groups,ICV(Sfrp5)+DVC(MK801)groups;sham Vx+ ICV(a CSF)groups,hep Vx+ ICV(a CSF)groups,sham Vx+ ICV(Sfrp5)groups,hep Vx+ ICV(Sfrp5)groups.blood was obtained and the rate of hepatic VLDL-TG secretion was measured following tyloxapol(an inhibitor of lipoprotein lipase)injection.Results: Central administration of Sfrp5 decreased significantly hepatic VLDL-TG secretion in rat with hypothalamic inflammtion,whereas NMDA receptor blocker MK-801 negated Sfrp5's effect.furthermore,ICV infusion of MK-801 alone did not modify the hepatic VLDL-TG secretion.meanwhile,hepatic vagotomy also nullified Sfrp5's effect.Conlusion: Central infusion of sfrp5 decrease hepatic VLDL-TG in rats with hypothalamic inflammation in dependent on brain-liver axis.Part?INTRACEREBROVENTRICULAR SFRP5 INFUSION DECREASE THE HEPATIC VLDL-TG SECRETION IN RATS FED WITH HIGH FAT DIET VIA INHIBITING HEPATIC SCD-1Aim: To detect the hepatic mechanism involved in hypolipidemic effect induced by ICV sfrp5.Methods: The liver tissue were obtained from ICV a CSF group,ICV glibenclamide group,ICV sfrp5 group and ICV(sfrp5+ glibenclamide)group.The expression of FAS,DGAT1,DGAT2,SCD1 and MTP in liver were detected by Western blot.Meanwhile,the expression of SCD1 of other groups were determined by Western blot also.Results: The expression of SCD1 in ICV Sfrp5 group were significantly lowered than other groups(p<0.01)..However,the expression of FAS,DGAT1,DGAT2 and MTP were unchanged(p>0.05).Conclusion: Central administration of sfrp5 lower hepatic VLDL-TG in rats fed with high-fat-diet via inhibiting hepatic scd-1.