Action And Mechanism Of FTZ Towards Glucose-lipid Metabolic Disorder Mice Modelcaused By Circadian Rhythm Disorders

Objective:To elucidate the mice model of glucose-lipid metabolic disorder induced by circadian rhythm disorders. Then we intervene in this modle with the compound Zhenzhu Tiaozhi capsule(FTZ) and study the probable mechanisms by the application of " the liver is the pivot to regulate the lipid and get rid of the waste" theory. Methods:1. Establishing circadian rhythm disorders mice model. 6 weeks of C57BL/6J male mice grouped four randomly, namely: control group(CON,8,Daytime light,Night dark), 24h-hour light group(24h L, 36,Daytime light,Night light), 24 h hours dark group(24h D, 36,Daytime dark,Night dark), feed and Light are restricted(RFL,36, Daytime dark night light), CON,24 h L,24 h D group fed a diet ad libitum,RFL group time-restricted feeding for daytime.The modeling time is 12 weeks. By dynamic monitoring of food intake during the day and at night, weight, glucose metabolism(FBG, FINS, OGTT, ITT), lipid metabolism(TC, TG, HDL-C, LDL-C) to evaluate if we establish a successful model.2. Study on the intervention effect and related mechanism of FTZ on circadian rhythm disorders mice model. Take the above 24 h D, 24 h L, RFL group of mice, each group were divided into 4 groups, each group of 8, namely: control group, positive drug group, high dose of FTZ group, low dose of FTZ group, a total of 13 groups,medicine for 8 weeks. Dynamic monitoring day and night food-intake, body weight of mice, The ninth week to determine all of the mice’s glucose-lipid metabolism indicators.Tenth week, according to the Zeitgeber Time(start light time recorded as ZT0), each group in the ZT0(8:00am), ZT6(2:00pm), ZT12(8:00pm), ZT18(2:00am) 4 time points(each 2) kill the mice, mice liver, epididymis fat, kidney fat were taken to calculate the organ index and fat body ratio and test the TC,TG levels in the liver;liver tissue was fixed and liver pathological tissue sections were made; Extracting the liver and expression of clock genes m Clock,m Bmall, m Cryl and lipid metabolism-related genes pparγwas detected by Real-time PCR. Results:1.After 12 weeks of modeling, CON,24 h L,24 h D group compared to the CON group, weight increased significantly(p<0.05); mice dietary pattern undergo changes, also day/night eating proportion; CON,24 h L,24 h D group TG, LDL-C, FBG, FINS were higher than group CON(p<0.05), 24 h L, 24 h D group TC levels were higher than those in the CON group(p<0.05), but the RFL group was not statistically significant(p>0.05),RFL group of HDL-C and CON group was significantly lower(p<0.05), however, 24 h L, 24 h D group was not statistically significant(p>0.05);compared with CON group, the ISI and HOMA-IR of CON,24 h L,24 h D group was significantly higher than that of the model group(p<0.05); In the OGTT experiment, there was no difference in blood glucose concentration between the groups at the same time(p>0.05), but the area under the curve of 24 h L, 24 h D group compared CON group was significantly higher(p<0.05), RFL group was not statistically significant(p>0.05), the ITT of CON,24 h L,24 h D group was significantly higher(p<0.05) than that of the CON group.2.After 8 weeks therapy, FTZ slightly reduced food intake in mice, the mice weight was downward trend(no significant difference); FTZ reduce serum TC, LDL- C, FBG, FINS level of LCON, DCON, RCON groups of mice(p < 0.05);After the treatment of FTZ, HOMA- IR, ISI, AUC(ITT) of LCON, DCON, RCON groups was improvement(p < 0.05), TC, TG level was decreased significantly in mice liver, body fat, body fat ratio and liver index was reduced,and have significant difference(p < 0.05),with varying degrees of ease LCON, DCON, RCON mice liver tissue lesions.But the effect of reducing serum TG, AUC(OGTT) of LCON, DCON, RCON groups of mice,and elevating of serum HDL – C of LCON, DCON, RCON groups of mice were not obvious(p > 0.05).LCON, DCON, RCON group compared with CON group, the total expression of liver tissue m Bmal1, m Cry1 and PPARγ gene or gene expression was increased and rhythm changed; FTZ can improve total Cry1 and PPARγ gene expression or restore its expressing rhythm, FTZ of Bmal1 gene expression rhythm is not obvious, but has influence on the amplitude. Conclusion:1、After 12 weeks change light or time of food intake in mice, constructing the glucose-lipid metabolic disorder mice model caused by circadian rhythm disorders2 、 After 8 weeks treatment,FTZ significantly improve the glucose-lipid metabolism of model mice,and the mechanism of its function may be by restoring liver Cry1 and PPARγ gene expression rhythm...