Regulation And Mechanism Of Adipose Tissue Function By The Transcription Factor ChREBP-?

With the accumulation of material wealth,obesity has gradually become a major health threat to human beings as a progressive metabolic disease.It has been reported that two billion people worldwide are overweight,and one third of them obese.Obese individuals typically exhibit increased adipose tissue,elevated levels of inflammatory response,and ectopic deposition of lipids.In addition,obesity is also a predisposing factor for type 2 diabetes,cardiovascular disease and cancer.The maintenance of the homeostasis of the body is the basic guarantee of health,and the occurrence of obesity is the result of the energy imbalance.Adipose tissue,as a metabolic regulatory organ with endocrine function,plays an important role in the body's energy homeostasis and obesity-induced metabolic diseases.Adipose tissue can be classified into white adipose tissue(WAT)and brown adipose tissue(BAT)according to function,while subcutaneous WAT can be converted into beige fat under the induction of cold or sputum receptor activator.Functionally,WAT mainly plays a role in regulating the metabolic homeostasis of the body through the storage and mobilization of lipids and the secretion of adipokines,while BAT and beige fat mainly consume energy by thermogenesis to maintain body temperature.In 2009,several independent laboratories reported that brown adipose tissue also exists in adults.In cold stimulation,the intake of glucose by healthy adult BAT will increase by about 15 times.This discovery has made people realize that by enhancing the function of BAT or stimulating browning of WAT to increase the body's energy consumption,can be a potential treatment strategy for obesity and related metabolic diseases.So,the regulation mechanism of the brown fat production function has become a research hotspot.Due to the continued attention of researchers in the field of adipose tissue thermogenesis,many advances have been made in this field in recent years.A clear understanding of the developmental sources and morphological structures of brown/beige fat had reached.The regulation mechanism of brown fat function is also clear.The thermogenic function of BAT is highly regulated by neuroendocrine,hormones,transcription factors,and dietary metabolic status.The discovery of these mechanisms has made it possible to apply BAT activation to anti-obesity.The carbohydrate response element binding protein(ChREBP)is highly expressed in brown fat,which has two subtypes ? and ?.ChREBP-? is an active form with low expression and is transcriptional regulated by ? subtype.ChREBP is a key transcriptional regulator of glycolipid metabolism in the liver,intestine and adipose tissue.It has been reported that ChREBP mediates T3 and high glucose-induced BAT thermogenesis.It has also been pointed out that in human BAT,the expression of ChREBP-? and Fasn is positively correlated with UCP1 expression.These reports suggest that ChREBP-? may play an important role in the activation of BAT.However,direct evidence for the regulation of BAT thermogenesis by ChREBP is not sufficient.The mechanism by which ChREBP affects BAT thermogenesis has not been reported.In order to further explore the regulation and mechanism of ChREBP-? on adipose tissue function,we firstly generated BAT and adipose tissue ChREBP-? overexpressing mice by Cre/Loxp approach,and systematically analyzed the phenotype and molecular mechanism.The main findings can be divided into the following aspects.1.Overexpression of ChREBP-? in adipose tissue improves the glucose and lipid metabolic homeostasis of mice.In this study,we examined the metabolic phenotype of mice overexpressing ChREBP-? in brown fat and whole adipose tissue,and found that overexpression of ChREBP-? in brown fat had no impact on metabolic phenotype of normal-fed and HSD-fed mice,but alleviated glucose intolerance induced by high fat diet.Overexpression of ChREBP-? in whole adipose tissue improved blood glucose and glucose tolerance on the one hand,and increased the specific gravity of gonadal white fat on the other hand.2.Overexpression of ChREBP-? in adipose tissue impair cold tolerance of mice.We used an acute cold exposure test to detect cold tolerance in mice.Mice with BAT overexpressing ChREBP-? were found to have a rapid decrease in body temperature two hours after exposure at 4?,and this phenotype was not affected by gender and age,implying that overexpression of ChREBP-? in BAT leads to impaired cold-adapted thermogenesis.After overexpressing ChREBP-? in whole adipose tissue,mice also had a cold intolerant phenotype and were more pronounced.It is suggested that the overexpression of ChREBP-? in WAT impaired its supplemental thermogenesis induced by cold stress.The body temperature of adipose tissue overexpressing ChREBP-? mice under high sucrose and high fat load decreased more rapidly than normal-fed mice.3.ChREBP-? overexpression in adipose tissue inhibits BAT thermogenesisTo explore the mechanism of cold intolerance in adipose tissue ChREBP-? overexpression mice,we examined various process of adipose tissue thermogenesis.We found that overexpression of ChREBP-? in BAT resulted in a “whitening” phenotype of BAT,such as enlarged droplet size and cell volume,decreased number of mitochondria,and a decrease in the expression of UCP1 and Dio2.It is the main mechanism by which ChREBP-? down-regulates the function of BAT thermogenesis.The renewal and autophagy of mitochondrion keep mitochondrion at a high average activity.We found that ChREBP-? overexpression inhibits mitochondrial fission,fusion and autophagy in BAT,which may be an important mechanism of BAT thermogenesis deficiency.In addition,in BAT from ChREBP-? over-expressed mice,the down-regulation of the fatty acid ?-oxidation-related gene Cpt1 also constitutes a part of the mechanism of BAT thermogenesis deficiency.In conclusion,ChREBP-? overexpression inhibits BAT thermogenesis by regulating the number and activity of mitochondria,fatty acid ?-oxidation related gene Cpt1,thermogenesis related genes UCP1 and Dio2.4.ChREBP-? overexpression in adipose tissue inhibits cold-induced adipose tissue remodelingAfter long-term cold training,BAT and WAT will undergo adaptive changes,which we call BAT remodeling and WAT browning.ChREBP-? overexpression inhibits the up-regulation of UCP1 induced by long-term cold training,and maintaining a "whitening" phenotype.The results of histology and m RNA detection also suggested that ChREBP-? overexpression inhibited long-term cold training-induced white fat browning.In summary,our data can be concluded as follows:(1)ChREBP-? in adipose tissue can improve blood glucose levels and glucose tolerance in mice,improve diet-induced metabolic disorders;(2)ChREBP-? in adipose tissue can reduce cold tolerance of mice;(3)ChREBP-? overexpression in adipose tissue inhibits BAT thermogenesis and WAT browning;(4)ChREBP-? inhibits adipose tissue thermogenesis at least partly by modulating thermogenic and fatty acid ?-oxidation gene expression and mitochondria biogenesis and function.