“TUDCA-ATF4-GDF15”调控轴在袖状胃切除术后食欲抑制中的作用及其机制研究

我国是肥胖症第一大国。袖状胃切除术（SG）可有效治疗肥胖症，术后食欲下降是体重减轻的主要原因，但具体调控机制不清楚。生长分化因子15 （GDF15）主要由肝细胞产生，是食欲的重要调控因子。课题组前期研究发现SG术后血清牛磺酸结合熊去氧胆酸（TUDCA）和GDF15显著升高。在此基础上，课题组结合国内外同行研究成果，提出假说：SG术后TUDCA升高，通过肝脏整合应激反应上调其关键效应分子ATF4，升高GDF15转录与合成，其通过血脑屏障激活中枢GFRAL，以抑制食欲并最终有效降低体重。本项目拟建立肥胖SG小鼠模型，应用高效液相色谱串联质谱、基因敲除、慢病毒转染等技术，从动物和细胞实验水平研究SG术后TUDCA升高对肝细胞整合应激反应中ATF4表达的作用，并探索其调控GDF15表达的机理，以期进一步揭示SG抑制食欲的分子机制，并为肥胖症的治疗探索新的靶点。

China has the largest population of obesity patients. Sleeve gastrectomy(SG) has gradually become a solid bariatric surgery procedure to treat obesity. Decreased appetite is a significant factor for weight loss after SG. Growth Differentiation Factor 15 (GDF15), an anorexic hormone secreted by the liver, is an essential regulator of appetite. Previous studies by our group found that tauroursodeoxycholic acid (TUDCA)and GDF15 were significantly elevated after SG. Based on these facts, we hypothesized that the increased TUDCA after SG would modulate ISR to upregulate the key molecule ATF4 in hepatocytes, leading to increased synthesis and release of GDF15, which activates GFRAL in the central nerve system, thus suppressing the appetite and finally resulting in weight loss. This project aims to investigate the effect of SG-induced increase of TUDCA on hepatocyte ISR and up-regulation of ATF4, especially the molecular mechanisms underlying ATF4 mediated GDF15 expression. The mechanisms will be validated in vivo and in vitro through establishment of a SG surgical model of obese mice and employ the methodology includingultra performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS), conditional liver specific gene knockout, and lentiviral transfection. This study will enable us to reveal the mechanisms of appetite inhibition after SG, and to determine new targets for the treatment of obesity.