Mechanism Of Adipogenesis And Insulin Resistance Improvment Regulated By Ninjurin2

Obesity is the most serious health problem worldwide and a major risk factor for various metabolic diseases and cardiovascular and cerebrovascular diseases.The dysfunction of adipose tissue in obese patients leads to peripheral insulin resistance,which reduces the uptake and utilization of glucose by the body,and increases the output of glucose in the liver,leading to the occurrence of hyperglycemia and even diabetes.Insulin resistance is the most important link between obesity and type 2 diabetes.Finding new regulatory mechanisms of adipose tissue function and insulin resistance may contribute to the development of new strategies for the prevention and treatment of diabetes.The causes of obesity are complex.Genetic factors play an important role in the obesity process.Previous genetic studies have shown that the NINJ2 gene(encoding the Ninjurin2protein)located on human chromosome 12p13 is associated with the risk of atherosclerosis.Moreover,genome-wide association analysis also showed that the single nucleotide polymorphisms(SNPs)regulating Ninjurin2 expression were significantly associated with obesity and metabolism-related phenotypes in the population.In addition,the humanderived NINJ2 transgenic overexpression mice constructed earlier by our research group showed obvious obese phenotype,while the Ninj2 knockout mice showed adipogenic differentiation abnormalities.The results show that the NINJ2 gene may be associated with obesity,but the underlying molecular mechanism is currently unknown.The Ninjurin2 protein consists of 142 amino acid residues.It has been found to regulate neuronal growth,tumor cell growth,and activation of vascular endothelial cells.The molecular mechanism of its regulation of obesity and related phenotypes is still unclear.This project mainly investigates the relationship between Ninjurin2 and preadipocyte differentiation,insulin resistance,glucose homeostasis and its regulatory mechanism through cell and animal models.First,this study constructed Ninj2 knockout mice and found that mice lacking Ninjurin2 had impaired adipogenesis,increased insulin resistance,and abnormal blood glucose homeostasis.Further studies have shown that the Ninjurin2 deletion can lead to impaired insulin-stimulated AKT-GLUT4 signaling.Under insulin treatment,the expression of phosphorylated AKT and glucose transporter GLUT4 in subcutaneous adipose and muscle tissue of Ninjurin2-null mice was reduced,suggesting that knockout of Ninjurin2 in mice can inhibit insulin signaling in adipose tissue and muscle.Subsequent cellular experiments revealed that Ninjurin2 could directly interact with the insulin receptor INSR and the insulin-like growth factor receptor IGF1 R,enhancing the activation of insulin signaling pathway core factors AKT.Phosphorylated INSR/IGF1 R and AKT levels in preadipocytes with Ninjurin2 deletion are reduced,and cell proliferation is decreased.Ninjurin2 deletion inhibited the expression levels of key transcription factors of adipocyte differentiation-CEBPβ,CEBPα,PPARγ and the ability of preadipocytes to differentiate into mature adipocytes,ultimately regulating adipogenesis.In addition,knockdown of Ninjurin2 in C2C12 cells inhibited INSR/IGF1 R phosphorylation levels and activation of the insulin signaling pathway,and affected insulin resistance in muscle cells.Finally,this study used an adenovirus vector to overexpress Ninjurin2 in high-fat-fed mice,which could improve the insulin sensitivity of epididymal fat,inguinal fat and muscle tissue in high-fat diet-fed mice,and significantly improved insulin resistance and glucose tolerance in mice.The above studies established Ninjurin2 as a new regulator of the insulin signaling pathway,and proposed a new regulatory mechanism for insulin signaling,adipogenesis and insulin resistance.It provides a new perspective for understanding the relationship between insulin resistance,obesity and type 2 diabetes,and developing new prevention and treatment methods for diabetes.