| Research BackgroundPatients with Type 2 Diabetes Mellitus(T2DM)are usually accompanied by varying degrees of overweight or obesity.With the increase of weight,the risk of patients with cardiovascular diseases also increases,and reducing the weight of patients can bring many benefits.Therefore,clinical weight management of diabetic patients has also received more attention.Glucagon-like peptide 1(GLP-1)is an endogenous peptide hormone.It is reported that it can regulate human blood sugar in a blood sugar-dependent manner,and it has been found to increase satiety,suppress appetite,reduce food intake,and reduce weight through the central pathway.However,the mechanism by which the central center regulates appetite and affects food intake has not yet been fully ascertained.GLP-1 secreted under physiological conditions will be degraded and inactivated by enzymes such as dipeptidyl peptidase 4(DPP-4)in the body in a very short period time,and stable clinical effects cannot be obtained.The new generation of hypoglycemic drug Exendin(Exendin-4,Ex-4)is a GLP-1 receptor agonist.It can activate the GLP-1 receptor in the body and produce the physiological effects of GLP-1 in regulating blood sugar and body weight,and is not affected by DPP-4.At present,it has been widely used in clinical practice,and its effect on weight reduction can be accurately observed.In addition,existing studies have shown that EX-4 can also prevent cell apoptosis,fight oxidative stress and inflammation,and improve the metabolic state of many organs.Some studies have shown that a high-fat diet can induce inflammation of the hypothalamus.By giving a fat-rich diet to increase food intake and weight gain,hypothalamic microglia inflammatory factors such as TNF-α,IL-6,IL-1β,etc.can be found to increase.The occurrence and progression of chronic inflammation of the hypothalamus may further aggravate the increase in food intake and obesity.Nuclear factor κB(NF-κB)is a protein that can regulate the body’s inflammatory response.It has been found that NF-κB in mammals includes five major members,namely p50(NF-κB)and p52(NF-κB2)protein,p65(Rel A),Rel B and Rel(c-Re1)protein.Among them,p50-p65 dimers are the most widely distributed,and they are usually used to refer to NF-κB.When NF-κB is at rest,the p50-p65 dimer binds to the inhibitor of NF-κB(inhibitor of NF-κB).IκB prevents NF-κB from mediated inflammation by covering the nuclear localization signal area NLS(Nuclear localization sequence)on NF-κB.When cells are stimulated by external inflammatory stimuli such as TNF-α,IL-6 and other cellular inflammatory factors,IκB is degraded through a series of reaction processes,exposing NLS,and NF-κB enters the nucleus and binds to specific sites on DNA,and activates NF-κB.After NF-κB is activated,it can induce the release of a variety of pro-inflammatory cytokines,chemokines,adhesion factors,etc.,leading to the production and aggravation of inflammation.Our previous studies have shown that administration of Ex-4 to the third ventricle can significantly reduce the food intake of obese diabetic rats.Through functional diffusion weighted imaging(f DWI)technology,it was observed that the hypothalamic feeding regulation area of obese diabetic rats showed changes in f DWI signals under the intervention of Ex-4.This suggests that the reduction of rat food intake may be related to the role of Ex-4 in the hypothalamic food intake regulation area.Is the effect of Ex-4 in reducing the weight of patients with type 2 diabetes related to its improvement of hypothalamic inflammation and metabolism? NF-κB p65,as a hypothalamic inflammatory factor,does its level change have any relationship with the intervention of Ex-4?Research PurposesBy observing the changes of NF-κB p65 in obese type 2 diabetes rat’s hypothalamus at different times after the intervention of Ex-4 and GLP-1 receptor blocker Ex-(9-39).To explore the relationship between Ex-4 intervention and hypothalamic inflammation in obese type 2 diabetes rats.Object and MethodAccording to weight and blood sugar,SD rats were divided into four different metabolic state groups: Obese Type 2 Diabetes(O2D,n=83)group,Obese non-Diabetes(OND,n=20)group,Non-obese Type 2 Diabetes(NO2D,n=22)group,Non-obese non-Diabetes(NOND,n=20)group.The four groups of rats all received the third ventricle catheterization and corresponding intervention.The rats in the O2 D group were divided into three groups according to the different intervention methods:the first group was directly given Ex-4(0.1ug/mouse)(O2D-1 group);the second group was given Ex-(9-39)(1ug/mouse),and then given Ex-4(0.1ug/mouse)(O2D-2group);the third group was given normal saline(NS,1ul/mouse)(O2D-3 group)intervention,and the other three groups were only given Ex-4(0.1ug/only)intervention.After the intervention,the hypothalamic tissues were collected at 0.5h,2h,8h and 24 h,and 3mm thick tissues were cut out and embedded in paraffin to prepare sections.Immunohistochemical and semi-quantitative methods were used to detect 3 different parts of the hypothalamus.Detect the content of NF-κB p65 in hypothalamic tissue.The changes of NF-κB p65 expression in hypothalamus tissues of rats with different intervention methods with feeding time and the differences between groups were compared.The SPSS 25.0 statistical software package was used for statistical processing,and P<0.05 was considered statistically significant.Results1.There are significant differences in the content of NF-κB p65 in the hypothalamus of the four groups of rats with different metabolic states.The content of NF-κB p65 in the hypothalamus of rats in the O2 D group was significantly higher than that in the NO2 D group at all time points after eating(P<0.05),and was significantly higher than that in the NOND group at 0.5h,2h,and 8h after eating(P,respectively are 0.033,0.002,0.000).2.After Ex-4 administration,the content of NF-κB p65 in the hypothalamus of rats in the O2 D group began to decrease significantly after 0.5h(all P<0.05),and it was at the lowest level at the second hour.The content of NF-κB p65 in the hypothalamus of the 4 groups of rats was significantly different at 0.5h and 8h after eating(P 0.007,0.032,respectively);O2D group and OND group at 0.5h The content of NF-κB p65 in the hypothalamus of rats was significantly higher than that of rats in NO2 D and NOND groups(both P 0.000).At 8h,the content of NF-κB p65 in the hypothalamus of the NO2 D group was significantly lower than that of the other 3groups(all P are 0.000)3.After the intervention of Ex-(9-39)in O2 D group,the ability of EX-4 to reduce the expression of NF-κB p65 in hypothalamus is significantly reduced.The content of NF-κB p65 in hypothalamus of rats treated with at Ex-(9-39)group and NS2 h,8h and 24 h after feeding was significantly higher than that in EX-4 group(P 0.000 for all),and the content of NF-κB p65 in hypothalamus of rats treated with Ex-4 is significantly decreased at 0.5h after feeding(P <0.05 for all).Conclusion1.Ex-4 third ventricle administration can significantly reduce the expression of NF-κB p65 in the hypothalamus of O2 D rats,it is at the lowest level in the 2h.2.The expression of NF-κB p65 in the hypothalamus of O2 D rats was not significantly different after Ex-(9-39)pretreatment with Ex-4 and direct administration of NS. |
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