Regulation And Mechanism Of Gab2 On High Fat Diet-induced Adipocyte Differentiation In Mice

White adipose tissue can store excess energy in adipose tissue in the form of triglycerides,and excessive accumulation of lipid droplets can lead to obesity.The process of obesity is accompanied with numerous complications,such as hypertension,Hyperlipidemia,insulin resistance,type Ⅱ diabetes,and cancer.At present,the treatment strategies for obesity is difficult to maintain,even had serious side effects.Therefore,it is urgent to find a new method to effectively treat obesity.Adipose tisssue not only store energy,but also participate in energy metabolism in the organism.Brownadipocytes and beige adipocytes are able to uncouple the oxidative respiration of mitochondria from the process of producing ATP with the help of uncoupling protein(UCP1),which allows excess energy to be dissipated as heat.Brown adipose tissue can regulate the body’s energy metabolism process,providing new insight for the treatment of obesity and related metabolic diseases.Gab2 protein is a scaffold protein which can mediates both receptor tyrosine kinase and non-receptor tyrosine kinasemediated signaling.Gab2 can integrate intracellular signal pathways when stimulated by extracellular signals to achieve rapid amplification of signals.Gab2 can participate in a variety of cancer,heart disease and immune function regulation;our previous work in the laboratory also found that Gab2 is involved in the liver’s glycolipid metabolism,knocking out of Gab2 can inhibit the development of fatty liver.There is little research on the Gab2 regulate adipocytes differentiation.Here,we explored that Gab2 can influence the differentiation of adipocytes,which can benefit for the resistance of obesity.Our study found that in high-fat diet-induced obesity,the expression of Gab2 in adipose tissue was significantly higher than that in the normal diet group;knockout of Gab2 reduced the body weight of mice fed a high-fat diet,whichmainly because Gab2 knockout reduces the weight of adipose tissue in mice;Loss of Gab2 can improve insulin sensitivity and glucose tolerance in high-fat diet-fed mice;The macrophage content in the visceral adipose tissue of the Gab2 knockout mouse is much lower than that of the wild type mouse.Knockdown of Gab2 can reduce the level of inflammatory factors in the circulation;knocking out Gab2 in mice can improve the function of BAT,as it also increases the expression of heat production gene.Gab2 deletion can increase the expression of brown fat characteristic genes during Stromal Vascular Fraction cell differentiation.Gab2 can affect the transcriptional activity of UCP1 target gene promoter stimulated by CL316,243.The regulation of UCP1 expression by Gab2 may be due to the binding of Gab2 to PI3K p85,which activates the downstream AKT-FOXO1 signaling pathway.These results indicate that Gab2 can regulate the differentiation and metabolic function of adipose tissue in obesity.Our study revealed the function of Gab2 in adipose tissue and found a new site of action for Gab2.In addition,as a potential therapeutic target,Gab2 also provides new ideas for the treatment of obesity and related metabolic diseases.