Basic Research Of The Feasibility Of Altering The Obesity Phenotype By Brown Adipose Tissue Transplantation And Targetting Myl2 Phosphorylation

BackgroundThe harm of obesity is not only in appearance,but also in the significant increase in the incidence of obesity-related diseases.Limited to the individual’s subjective initiative,a balanced diet and regular exercise to lose weight have limited effects on most people.Invasive methods such as liposuction and gastrectomy have their own risks,which limit their development on a larger scale.However,the weight-loss drugs currently approved by the FDA have more or less adverse reactions.Therefore,how to safely and effectively increase the basal metabolic rate has become the focus of the obesity research field for the last ten years.The biggest feature of brown adipose tissue is non-shivering heat production,which is an important way to increase the energy consumption of the body without relying on muscle unit exercise in the resting state.The activity of brown adipose tissue in obese elderly people decreases compared with young people of normal weight.In specific,the effect of whitening brown fat on the improvement of basal metabolic rate after being activated with cold etc.is significantly reduced.This study verified the whitening of brown adipose tissue in obese model mice,and tried to use two different methods of brown fat transplantation and target regulation to reverse the whitening of brown fat in obesity,and provide the theoretical support for the ultimate clinical application in the treatment of obesity phenotypes.Methods1.The difference analysis of brown adipose tissue in ob/ob mice and C57 mice before and after cold induction.Ob/ob obese mice and C57 mice were kept at room temperature and 4℃,and the changes in histology,browning gene transcription level,imaging and metabolism of the two groups of brown adipose tissue were observed.2.Feasibility analysis of brown fat allogeneic transplantation to improve obesity phenotype.The brown fat and white fat of C5 7 mice were transplanted to the scapula of ob/ob mice,and the improvement of the obesity of the two treatment groups and the outcome of the graft itself were observed.In vitro anaerobic culturing model was applied to test the anti-apoptotic ability of brown adipocytes and white adipocytes.3.In vivo and in vitro studies on the obesity improvement by targeting the phosphorylation of my12 protein to regulate the differentiation of brown adipose derived stem cells.The target gene my12 was screened out by the gene chip and the differential expression level of its phosphorylated protein was verified in ob/ob mouse and C57 mouse brown adipose derived stem cells.The inhibition of my12 phosphorylation was used to detect its regulatory effect on the differentiation of brown adipose derived stem cells in vitro.Finally,the overexpression of myl2 was used to verify its obesity improvement effect on ob/ob mice in vivo.Results1.Compared with the brown adipose tissue of C57 mice,the brown adipose tissue of ob/ob obese mice has weakened structure and decreased function in histology,browning gene transcription level,imaging and metabolism,and the difference is magnified after cold stimulation.2.Ob/ob mice transplanted with brown fat showed improvement in their obesity phenotype in the short-term,but the obese parameters of these mice grew rapidly again after the 10th week of transplantation.Brown fat grafts have whitening and decreased retention.In vitro experiments have found that brown fat cells are more prone to apoptosis under hypoxia.3.Phosphorylated My12 protein is under-expressed in ob/ob mouse brown adipose derived stem cells.Inhibition of the phosphorylation of my12 affects the differentiation of brown adipose derived stem cells in vitro,while overexpression of my 12 protein and its phosphorylation level can improve the obesity phenotype of ob/ob mice for a long time in vivo.ConclusionsThe brown adipose tissue function of obese model mice was significantly impaired due to whitening.Orthotopic transplantation of brown fat can improve the obesity phenotype of ob/ob mice in a short period of time,but with the whitening of the grafted brown fat and the decrease in retention volume,ob/ob mice receiving brown fat transplantation will return to obesity phenotype.Phosphorylated My12 protein can participate in the differentiation of brown adipose derived stem cells,and targeting my12 phosphorylation can regulate the differentiation process and inhibit the whitening of brown fat,which is a feasible solution to improve the obesity phenotype.