胃肠能量感受分子mTOR在胃旁路手术术后胃肠激素合成以及血糖调节中的作用研究

Roux-en-Y gastric bypass, RYGB, is the most effective management to improve glycemic control in morbidly obese patients with type 2 diabetes. The weight loss and relatively swift improvement of glycemic status that follow RYGB are thought, in large part, to be the result of RYGB-induced rerouting of nutrients, which in turn is thought to alter the secretion of gastrointestinal hormones. However, the molecular mechanisms by which postoperative endocrine cells sense fuel status at the organism level to regulate hormone production and glucose metabolism are currently unknown. Our previous studies indicate that the mammalian target of rapamycin signaling pathway in the gastrointestinal mucosa is crucially involved in fuel sensing in the gastrointestinal tract and plays a critical role in the coordination of nutrient availability and ingestive behavior via the production of gastrointestinal hormones such as ghrelin and glucagon like peptide-1(GLP-1). Furthermore,gastrointestinal mTOR activity is activated by Roux-en-Y gastric bypass in both rodents and human being. The major focus of this proposal is to investigate the function of the gastrointestinal mTOR pathway in postoperative gastrointestinal endocrine network and thus its effect on blood glucose control. We propose to use pharmacological and molecular biological techniques to achieve these goals. Completion of this proposal will therefore yield new insights relevant to treatment strategies for diabetes. Restoring the homeostasis of the gastrointestinal endocrine and fuel sensing network is appealing if we want to provide a safe and effective therapy in the setting of obesity and diabetes by “pharmaceutical gastric bypass”.

胃旁路手术治疗肥胖合并2型糖尿病疗效显著，与手术改变胃肠道解剖结构后影响胃肠内分泌有关。术后胃肠道如何感知机体能量状态继而调控胃肠内分泌、影响糖代谢尚不清楚。申请人前期工作发现胃肠存在以mTOR为中心的能量感受机制，通过感受机体能量状态来调控胃肠激素ghrelin、GLP-1合成分泌。预实验提示人、小鼠行胃旁路手术后胃肠mTOR活性显著升高。本课题采用药物干预、基因修饰（内分泌细胞和L细胞特异性TSC1基因敲除）等手段改变小鼠胃肠mTOR活性，观察胃旁路手术在胃肠道mTOR活性改变后对胃肠内分泌以及糖代谢的影响。同时观察肥胖患者手术前后胃肠标本mTOR活性以及胃肠激素合成的变化。探讨胃肠能量感受分子mTOR在感受胃肠解剖结构重塑后能量状态的改变、调控术后胃肠内分泌以及糖代谢中的作用及其分子机制。为揭示胃旁路手术治疗糖尿病的分子机制以及筛选胃肠为靶向的“药物性胃旁路”提供新理论依据。

胃旁路手术治疗肥胖合并2型糖尿病疗效显著，与手术改变胃肠道解剖结构后影响胃肠内分泌有关。术后胃肠道如何感知机体能量状态继而调控胃肠内分泌、影响糖代谢尚不清楚。本课题研究发现胃肠存在以mTOR为中心的能量感受机制，感受机体所处的能量状态。人、小鼠行胃旁路手术后胃肠mTOR活性显著升高。术后被活化的胃肠能量感受机制是导致胃组织ghrelin合成减少并刺激肠道合成释放GLP-1的关键因素。从而解释了胃旁路手术减重、降糖的具体分子机制。我们的以上发现为揭示胃旁路手术治疗糖尿病的分子机制以及为筛选以胃肠为靶向的“药物性胃旁路”提供新理论依据。相关工作发表于EBioMedicine(2018年），Cell Physiol Biochem（2018年）。此外，研究还发现，RYGB手术激活患者、小鼠肝脏mTOR活性，继而通过Insig2a-AKT2-SREBP1c通路抑制脂肪酸从头合成，改善脂肪肝，此部分工作发表于Biochim Biophys Acta Mol Basis Dis（2019年）。