The Mechanism Of Prebiotics And New Adipokine In Obesity

Background:Obesity is a significant problem in China and the rising prevalence calls for preventive strategies to defuse the health problem.The link between gut microbiota and development of obesity is becoming clearer.Grape seed proanthocyanidins extract(GSPE)is famous for its antioxidant properties,but the metabolic benefits of GSPE remain obscure.Brown adipose tissue and the browning process contribute to energy expenditure,resulting to protect against obesity.Although bone morphogenic proteins(BMPs)regulate adipogenesis,there is no report about GREM2,which is a natural antagonist of BMPs in metabolic disorders.Objective:We aimed to explore the regulation role of gut microbiota and browning process in obesity.In the first part,we focused on a potential prebiotic,GSPE,and demonstrated the beneficial metabolic effect which linked with gut microbiota.In the second part,we aimed to illustrate the correlation between serum GREM2 level and obesity in humans and further to explore the molecular mechanism of GREM2 in vivo and vitro.Methods:In the first part,the high-fat diet-fed mice were administrated with GSPE and PBS as controls.The we explored the role of GSPE on body weight,fat mass,glucose tolerance and the anti-inflammatory effect.16SrDNA was used to detected the gut microbiota changes.We next explored the metabolic effect of GSPE after using antibiotic cocktail,which could suppress the gut microbiota.In the second part,we detected the serum GREM2 level in normal controls and obese patients.The expression level of GREM2 in obesity and browning process was explored in vivo and in vitro.In stromal vascular fraction(SVF),we treated with GREM2 and detected the regulation role of GREM2 in brown adipocyte differentiation.We also used GREM2 transgenic mice and adipocyte-specific GREM2 knockout mice to further investigate the function of GREM2 in white adipose biology and white-to-brown fat transition.Results:In the first study,supplementation with GSPE significantly decreased the plasma levels of inflammatory factors such as TNF-?,IL-6 and MCP-1,companied with ameliorated macrophage infiltration in epidydimal fat and liver tissues.Furthermore,GSPE also reduced epidydimal fat mass and improved glucose tolerance.16SrDNA analysis revealed that GSPE supplementation modulated the gut microbiota composition and certain bacteria including Clostridium ??a,Rosburia and Prevotella.More importantly,depleting gut microbiota by antibiotics treatment abolished the beneficial effects of GSPE on inflammation and adiposity.In the second study,we have identified a novel adipokine GREM2,which can be secreted by adipocytes,are elevated in the plasma and adipose tissues of obese subjects and associated metabolic disorders.And each 1 SD increased in serum GREMs levels conveyed 1.5-fold higher risks of obesity after adjustment for multivariate factors.The higher level of GREM2 was also companied with obese mice and the lower level of GREM2 was detected in browning models.Administration of GREM2 inhibited the browning process of primary pre-adipocytes.Reduced Ucpl expression was achieved in GREM2 transgenic mice while enhanced Ucpl expression was observed in adipocyte-specific GREM2 knockout mice.Conclusion:Our study identifies the novel link between gut microbiota alterations and metabolic benefits by GSPE supplementation,providing possibilities for the prevention and treatment of metabolic disorders by targeting gut microbiota through a potential prebiotic agent GSPE.Our data revels that GREM2,as a new adipokine,which is for the first time detected in serum,regulates white-to-brown fat transition and plays an important role in the development of human obesity,which potentially contributes to the diagnosis and treatment of obesity in future.