The Effect Of Swimming Exercise And Diet Control On ApoE-/-mice Hypothalamus Inflammation And Its Correlation With SIRT1-NF-κB-GnRH Pathway

Objective:To explore the effect of swimming exercise and diet control on the hypothalamic inflammatory response in ApoE-/-mice and its correlation with SIRT1-NF-κB-GnRH pathway.Method:ApoE-/-mice were randomly divided into three groups,a high fat diet group(HFD group),a diet control group(DC group),and a swimming exercise group(EX group).Wild type mice served as a control group(con group).After 12 weeks of high-fat diet induction in ApoE-/-mice,a mouse model with a hypermetabolic syndrome phenotype was successfully established.The HFD group continued to be fed a high fat diet,the DC group and the EX group changed to a normal diet,and the EX group mice performed swimming for eight weeks.Mice were monitored for weight changes weekly.Morphological changes of mouse liver and calf gastrocnemius muscles observed by HE staining.Blood samples were taken to detect the concentrations of TC,TG,LDL,HDL and glucose in serum and the levels of IL-1β,TNF-α,MMP2,MMP9,SIRT1.Western blot was used to detect the expression of SIRT1,NF-κB,TNF-α,and IL-1β in the hypothalamus.Immunohistochemistry was used to observe the expression of Iba1,GFAP,and GnRH in the arcuate nucleus of the hypothalamus.Object recognition test detects space exploration and learning and memory in mice.Result:(1)Body weight and blood lipids: Compared with the con group,the HFD group had significantly increased body weight(P﹤0.01),serum TC,TG,LDL increased,and HDL decreased(P﹤0.01).Compared with the HFD group,the DC group and the EX group lost weight(P﹤0.01),and their blood lipids improved.Compared with the DC group,the EX group lost weight(P﹤0.01),TG level decreased(P﹤0.05),and HDL increased(P﹤0.01).(2)Serum Inflammatory factors: The serum cytokines IL-1β,TNF-α,MMP2,and MMP9 in the HFD group were higher than those in the control group,and SIRT1 was decreased(P﹤0.01).DC group and EX group had lower inflammatory factors and higher SIRT1 than HFD group,and the EX group had lower TNF-α and MMP9 than the DC group(P﹤0.05)and SIRT1 increased(P﹤0.01).(3)Liver morphology: The liver tissue structure of the HFD group is more disordered than that of the control group,and the liver lobular structure of the HFD group is not obvious.Hepatocyte edema and fatty degeneration appeared in the high-fat diet group,while the liver shape in the DC group and the EX group improved in the HFD group,and the EX group was more densely arranged than the DC group,and the hepatocytes had less steatosis.(4)Gastrocnemius morphology: The gastrocnemius muscle cells in the non-exercise group are loosely arranged,such as the HFD group and the DC group.And the gastrocnemius muscle cells in the EX group are neat and regular,and the cells are compact.Compared with the DC group,the gastrocnemius nucleated inflammatory cell infiltration was reduced in the EX group.(5)Hypothalamic protein expression: Compared with the con group,SIRT1 protein expression in the HFD group was reduced(P﹤0.01)and inflammation expression was increased(P﹤0.01).SIRT1 protein expression in DC group and EX group increased(P﹤0.01)and inflammatory protein expression decreased(P﹤0.05)than HFD group.Compared with the DC group,SIRT1 protein expression in the EX group increased(P﹤0.01)and inflammatory protein expression decreased(P﹤0.05).(6)Expression of Iba1 and GFAP in hypothalamic glial cells: The number of Iba1 and GFAP-positive cells in the HFD group was significantly higher than that in the con group(P﹤0.01).The expression of DC group and EX group was lower than that of HFD group,and EX group was significantly lower than that in DC group(P﹤0.05).(7)GnRH expression in the hypothalamic arcuate nucleus: Compared with the con group,the expression of GnRH in the arcuate nucleus of the HFD group was significantly reduced(P﹤0.01).Compared with HFD group,GnRH expression increased in DC group and EX group,and EX group expressed more obvious than DC group,and the difference was statistically significant.(P﹤0.05).(8)Object Recognition Test: The 1-hour and 24-hour discrimination index of new objects in the HFD group were significantly lower than those in the control group(P﹤0.01).Compared with the HFD group,the discrimination index in the DC group and the EX group increased significantly(P﹤0.01).Compared with the DC group,the discrimination index of the EX group increased(P﹤0.01).Discussion:Swimming exercise combined with diet control can alleviate chronic inflammation and delay aging caused by high fat diet,and improve cognition,which may be closely related to the hypothalamic SIRT1-NF-κB-GnRH pathway.