Recombinant Human GLP-1 Beinaglutide Regulates Lipid Metabolism Of Adipose Tissues In Diet-induced Obese Mice

Glucagon-like peptide-1 receptor agonists(GLP-1RAs)are a class of glucose-lowering agents with multiple benefits in diabetes,such as weight loss of obesity.Due to their characteristics of significant therapeutic effect and superior safety performance in clinical,it has attracted more and more attention recently.Beinaglutide is a recombinant human GLP-1(rh GLP-1)that shares almost 100% homology with human GLP-1(7-36).Clinical studies have shown that BN reduces body weight and body mass index(BMI)in overweight and obese T2 DM patients.But its role in lipids metabolism of adipose tissues remains to be elucidated.The dynamic alterations in lipid composition play a pivotal role in the changes in tissue function,which are closely linked to whole-body energy metabolism.The aim of this study was to determine the actions of rh GLP-1 BN in the insulin sensitivity and lipids metabolism of adipose tissues.Methods:Firstly,metabolic phenotypes of the obese mice after BN treatment were tested systematically.Obese Mice,which induced by high fat diet,were injected BN or Vehicle subcutaneously.Glucose tolerance,insulin sensitivity and insulin signaling pathway of the adipose tissues was measured.The body composition and whole body energy expenditure was measured after drug injection.Body temperature was detected every 1 hour after mice was explored to cold environment.The thermogenesis related genes and proteins was tested by real time PCR and Western blotting.Secondly,the lipids metabolism in three adipose tissues was deeply detected by lipidomic and RNA sequencing.Lipomics was applied to investigated the role of BN on lipids component of adipose tissues.RNAseq was applied to investigated the transcriptome profiles change after BN treatment.Results:Firstly,We have shown that BN improved the metabolic phenotypes of the obese mice,which was induced by HFD.Mice treated with BN have a lower food consumption and body weight.Glucose tolerance test and insulin sensitivity was improved in obese mice after BN treated.In the presence of insulin,BN enhanced the activation of insulin signaling pathway in vitro and in vivo.BN reduced lipids accumulated in adipose tissue and liver in mice fed with high fat diet.When explored to cold,the temperature of BN treated mice was higher than control mice.The thermogenesis related proteins and genes expression were improved.The basal metabolic rate(BMR)of BAT and SAT was higher in BN treated mice.Scecondly,lipidomic shown that BN treatment caused significant changes in content and composition of different lipid classes.Corresponding to lipidomic,RNA-seq shown that the expression of genes in lipid metabolic pathways in the adipose tissues.Conclusions:To summarize,this study shows that rh GLP-1 BN reduces HFD-induced body weight gain,and decreased lipids accumulation in the adipose tissues and the liver.Additionally,BN treatment increases insulin sensitivity of adipocyte in vivo and in vitro.Furthermore,BN treatment leads to marked changes in the composition of lipids and the expression of genes involved in lipid metabolism in the subcutaneous adipose tissues.Our results suggest important roles of rh GLP-1 BN on lipid metabolism and insulin activity in adipose tissues,and BN could alleviate obesity associated fatty liver and dyslipidemia by improving the function of adipose tissues.