The Study Of Role And Mechanism Of Aryl-hydrocarbon Receptor Repressor In Glucolipid Metabolism And Obesity

In recent years,the incidence and mortality of coronary heart disease have been increasing year by year and tending to be younger.Obesity is the main risk factor of coronary heart disease.It is a complex metabolic systemic disease accompanied by lipid and metabolic abnormalities.It is a physiological dysfunction of the human body caused by environmental,genetic and endocrine reasons.The pathophysiology of obesity has been found to be also related to the activation of aryl hydrocarbon receptor(AHR)caused by abnormal inflammatory state,and AHR and its downstream pathway factors may be involved in obesity and related lipid metabolism abnormalities.AHR repressor(AHRR)is an inhibitory factor of AHR,combined with the previous findings of our research group,we speculated that AHRR is also related to obesity.However,there are no complete studies on the effects of AHR and AHRR on obesity and metabolism,especially at the level of brown fat.Therefore,systematic studies are needed to prove the relationship between AHRR and obesity and metabolism.In Chapter 1,520 CHD patients were included as the discovery group and 556 patients as the validation group.Linear regression was used to find and verify the correlation between DNA methylation sites on AHRR gene and body mass index(BMI)and blood glucose and lipid-related indicators.It could also find AHRR CpG loci affecting BMI and glucose and lipid related indexes in Chinese population and explore the potential mechanism of AHRR influencing obesity in patients with coronary heart disease by influencing glucose and lipid levels.In chapter 2 and 3,fat-specific overexpression of AhRR mice and AhRR knockout mice were constructed based on the animal model of obesity induced by high fat diet.AHR inhibitors a naphthalenone and Bay-2416964 were used as the reference,and AHR inhibitor was administered to AhRR knockout mice by gavage.The mice were weighed regularly,and the feed intake and organ tissue indexes of the mice were detected.Blood glucose of each group was detected.Oral glucose tolerance Test(OGTT)and Insulin tolerance test(ITT)were tested.Total fat content,lipid index,fat cell volume,lipid accumulation in liver and mRNA expression level of brown fat related genes were detected.The AhRR overexpression and AhR knockout cell models of 3T3-L1 cell line were constructed to detect the levels of lipid metabolism indexes in the cells.The expression levels of obesity-related genes,heat-producing genes,fatty acid oxidation genes,lipid-cracking genes and other specific brown fat genes were detected.Investigating the metabolic phenotype of AhRR overexpressed and knockout mice fed with high fat.Determining the effect of AhRR gene on glucose and lipid metabolism.Investigating the mechanism of AhRR regulating lipid metabolism.The results showed that adipose tissue-specific overexpression of AhRR effectively inhibited obesity and insulin resistance induced by high fat diet in mice,reduce the lipid metabolism disorder caused by high fat diet.Conversely,AhRR-knockout can aggravate obesity and insulin resistance induced by high fat diet,aggravate the disorder of fat metabolism in mice caused by high fat diet.Intervention with AHRR-knockout mice with AHR inhibitors can reverse obesity and insulin resistance induced by high fat diet.Reduce the lipid metabolism disorder caused by high fat diet in mice.Overall,our study provides a new direction for the role of AHRR gene in the occurrence and development of obesity and the related molecular mechanism,and provides a reference target for the treatment of obesity.