Role Of New Adipokine GREM2,environmental Endocrine Disruptor Bisphenol A In Obesity

Context:Brown adipose tissue dissipates energy through heat and functions as a defense against cold and obesity.Factors that inducing the browning of white adipocytes could be apromising therapeutic pathway for the treatment of obesity.Previous studies have shown that BMP signaling pathway could play a pivotal role in brown fat adipogenesis.Thenatural BMP antagonist GREM2 could be related to metabolism,yet current researches were limited.Obesity is a complex disease resulting from genes and environmental factors.Environmental endocrine disrupting chemicals have been shown to be associated with higher risk for obesity.A growing body of epidemiological studies have shown that Bisphenol A(BPA)was positively associated with obesity.However,the mechanisms remain unclear.Objectives:We aimed to explore the pathogenesis of obesity from both genes and environmental factors.The first part of our study focused on exploring the association between new adipokine GREM2 and obesity and the mechanisms involved.The second part of the study explored the association between BPA exposure and obesity and the role of BPA in people with different BMI.Methods:In the first section,we enrolled 167 cases of obese subjects and 147 cases of normal weight controls.Serum levels of GREM2 and the association between GREM2 and obesity were determined.Then,Grem2 expression profile was determined in isolated tissues.We used primary cells,after Grem2 over-expression or knockdown,todemonstrate the important role of Grem2 in adipogenesis.In the second part of the study,five-week-old C57BL/6J mice were divided into 5 groups and administered with chow diet or high fat diet with or without BPA for 30 days to study the effects of BPA on body weight.Then we explored the role of BPA on adipogenesis,lipogenesis and chronic inflammation.Finally,we recruited 114 subjects with BMI<23.0kg/m~2 and 114 subjects with BMI>25.0 kg/m~2 sampling from Baoshan district to determine inflammation levels with quartiles of serum BPA.Results:We found that the natural BMP antagonist GREM2 was significantly increased in the serum of obese patients than normal-weight controls.GREM2 was positively correlated with the severity of obesity.Multiple linear regression analysis showed that serumGREM2 levels was independently positively associated with BMI and waistcircumference even after adjusting for many confounders.Grem2 was highly expressed in mature visceral adipocyte in normal chow diet mice,but little Grem2 was detected insubcutaneous fat.However,there was a significant increase of Grem2 expression in subcutaneous fat in mice after 12 weeks of high fat diet.Consistently,there was more GREM2 expression in subcutaneous fat in obese patients than that of normal controls.Further study has suggested that Grem2 may regulate adipogenesis and obesity byinhibiting canonical BMP/Smad signaling pathway.We observed a significant increase in body weight and fat mass in mice with all doses of BPA containing diet compared with BPA free diet in normal chow group.However,these results were not observed in high fat diet group.To further study the mechanism of BPA induced adiposity,we found BPA could potentiate adipogenesis,lipogenesis and chronic inflammation in adipose tissue.Human study revealed that the participants in the highest quartile of BPA had the highest level of serum Leptin,TNF?in participants with BMI under 23.0 kg/m~2,suggesting BPA exposure could increase general inflammation level,however,this association was not observed in those with BMI higher than 25.0 kg/m~2.Conclusion:Taken together,our study for the first time revealed that increased GREM2 was responsible for obesity by regulating brown adipocyte differentiation.On the other hand,our study demonstrated that BPA exposure could increase body weight and adiposityprobably by promoting adipogenesis,lipogenesis and chronic inflammation in adipose tissue.Our study will provide a new candidate GREM2 for the pathogenesis andtherapeutic target of obesity.And also we provide new evidence for the effects of BPA in metabolism.