Integrin αV Mediates The Effects Of Irisin On Human Mature Adipocytes Browning

Objectives:Obesity has become an important public health problem globally,but the cause has not been fully explained and there is no effective treatment.Obesity is a chronic metabolic disease characterized by excessive accumulation of body fat and excess weight.There are two types of adipose tissue with different function,white adipose tissues(WAT)and brown adipose tissues(BAT).WAT store energy in the form of triglycerides,while BAT consumes energy as heat through specific uncoupling protein 1(UCP1),thus reducing body weight and improving metabolism,so increasing BAT activity in humans has been a promising way in obesity treatment.The classical brown adipocytes are rare in adults,but some types of adipocytes in WAT can be induced to characterize like brown adipocytes by cold and sympathetic stimulation,these cells are defined as "beige adipocytes",and the process of promoting the transformation of beige adipocytes is defined as "adipose tissue browning".Irisin is a myokine secreted by skeletal muscle,and was reported to modulate adipocytes thermogenesis and influence whole body metabolism.However,data about the association of irisin with obesity and glucose metabolic status in humans remains controversial,and limited data are available concerning the Chinese population.And whether there is difference in the effects of irisin on adipocytes derived from different depots remains unknown,and the receptor of irisin on adipocytes is still unclear.This study aimed to evaluate the association between serum irisin concentrations and obesity,as well as glucose metabolic and cardiovascular factors in the middle-aged physical activity-matched Chinese Han race population,determine the browning effect of irisin on adipocytes of subcutaneous and visceral human adipose tissue,and explore the possibility that integrin αV was the receptor of irisin on human adipocytes.Methods:A total of 740 participants were included for serum irisin assay using ELISA in this cross-sectional study,who were divided into a normal weight(NW)group,overweight/obese(OB)group,normal weight type 2 diabetes(DM-NW)group and overweight/obese diabetes(DM-OB)group,and physical activity was evaluated and matched for the four groups.Circulating irisin levels were analyzed and compared among the groups with different adiposity and glucose status.Linear regression analysis was performed to test the relationship between serum irisin and adiposity indices,glucose metabolic and other cardiovascular risk factors.A total of 71 cases of wasted subcutaneous and visceral adipose tissue were collected from surgery.Human adipose tissue stem cells(hADSCs)were isolated from human subcutaneous and visceral white adipose tissues and induced to differentiate into mature adipocytes,the expression of UCP1 and thermogenic genes in mature adipocytes were examined with or without irisin treatment and compared between groups of different adiposity and different spots.Immunoprecipitation analysis was used to detect the interaction between irisin and integrin αV on adipocytes,and the protein expression of integrin αV in adipocytes was also compared between normal weight subcutaneous adipose group(NW-sub),obese subcutaneous adipose group(OB-sub),normal weight visceral adipose group(NW-vis)and obese visceral adipose group(OB-vis)groups.Results:Circulating irisin level was positively correlated with adiposity markers,including BMI,waist circumference and fat mass,and other cardio vascular risk factors,such as plasma triglyceride and low-density lipoprotein cholesterol level(p<0.01).Patients with type 2 diabetes had lower irisin levels compared to non-diabetes participants,in either normal weight or obese group,resulting in a positive correlation of irisin with HbA1c,HOMA-IR,and negative correlation with HOMA-IS(P<0.01).Linear regression analysis showed serum irisin levels were independently associated with sex,BMI,HbA1c,HOMA-IR and HOMA-IS(R2=0.465).Irisin treatment could increase the expression of beige adipocyte marker protein UCP1 and specific thermogenic genes in mature adipocytes derived from subcutaneous white adipose tissue,but not in visceral adipose tissue.The results of immunoprecipitation showed that irisin could attached to integrin αV on mature adipocytes,and there was no significant difference in the gene and protein expression of integrin αV in adipocytes,either derived from subcutaneous and visceral adipose tissue,or derived from obese and normal weight individuals(P>0.05).Conclusion:The results of present study indicated that circulating irisin was affected by adiposity and glucose metabolism condition in the middle-aged Chinese population.The increase of irisin under conditions of obesity may indicate its physiological function to improve glucose tolerance which is often impaired in obese subjects,but this compensatory secretion of irisin seems may not work once diabetes developed.Irisin contributed to the transformation of mature white adipocytes to beige adipocytes in human subcutaneous adipose tissue,but not in visceral adipose tissue.Integrin aV may mediate the browning effects of irisin on human mature adipocytes,which could provide the potential therapeutic targets for obesity and metabolic syndrome by promoting human brown adipose tissue activity,but the integrin aV gene and protein expression levels in human adipose tissue are independent of individual adiposity and anatomic position.