基于TGR5-mTOR信号通路探讨间歇性禁食改善胰岛素抵抗和糖代谢的分子机制研究

Intermittent fasting, a periodic energy restriction, has been a popular way to lose weight. However, our understanding of the underlying mechanism of intermittent fasting on glucose homeostasis is unclear. TGR5 has been identified as a membrane bile acid-activated G protein-coupled receptor which is involved in glucose homeostasis and immunomodulation. Our previous study found that bile acid metabolism was greatly changed in obese individuals with type 2 diabetes and obese subjects with type 2 diabetes after metabolic surgery. Here, we further investigated the mechanism of intermittent fasting on insulin resistance and glucose homeostasis on the basis of previous studies. Here we show that intermittent fasting could improve inflammation of adipose tissue and glucose homeostasis in diet-induced obese mice. Significantly altered bile acids induced by intermittent fasting and TGR5 siRNA will be used in adipose tissue macrophages to clarify the benefical effects of intermittent fasting through TGR5 activation. To elucidate the mechanism of intermittent fasting ameliorating adipose inflammation through TGR5-mTOR pathway, we conduct further more research in Tgr5–/– mice after intermittent fasting and in macrophages. Overall, these studies will provide a new evidence for intermittent fasting on improvement of glucose homeostasis and this dietary intervention has the potential to be therapeutically exploited for treatment of type 2 diabetes.

间歇性禁食作为一种周期性的能量限制方法，是目前比较流行的减重方法。但间歇性禁食改善糖代谢的具体机制尚不明确。研究发现胆汁酸可以激活其细胞膜受体TGR5在糖代谢和免疫调节中发挥重要作用。本课题组前期研究发现肥胖糖尿病患者及代谢手术干预后的糖尿病患者的胆汁酸代谢发生了明显变化。本项目拟在前期工作的基础上，深入研究TGR5信号通路在间歇性禁食改善胰岛素抵抗和糖代谢的作用机制。本项目将通过间歇性禁食干预的肥胖小鼠模型、体外添加胆汁酸和TGR5 siRNA干预的细胞实验证明该饮食引起的胆汁酸变化通过激活TGR5来减轻脂肪组织炎症和改善糖代谢；并进一步通过饮食干预的Tgr5–/–小鼠和体外细胞实验阐释TGR5-mTOR信号通路在间歇性禁食改善脂肪组织炎症中的作用机制。本项目的实施为间歇性禁食改善糖代谢提供新的理论依据，同时也为2型糖尿病的临床治疗提供新的思路和方法。

间歇性禁食作为一种周期性的能量限制方法，是目前比较流行的减重方法。但间歇性禁食改善糖代谢的具体机制尚不明确。本项目通过对高脂饮食诱导的肥胖小鼠进行间歇性禁食干预，发现间断性禁食可以减重，减少脂肪组织的累积及改善胰岛素抵抗。间歇性禁食干预后高脂饮食诱导的肥胖小鼠附睾周围脂肪组织的巨噬细胞标志物TNFα、Itgax、CCL-2、Mrc-1、Arg-1 mRNA表达在IF禁食干预后显著下降。经过间歇性禁食干预后，高脂饮食小鼠的肠道菌群结构发生了显著变化，厚壁菌门的丰度显著下降，疣微菌门的丰度明显增加，尤其是 Akkermansia、Verrucomicrobiales、Coprobacillus菌。而且间歇性进食干预后，小鼠血清总胆汁酸水平明显升高，其中以次级、结合胆汁酸升高为主。因此，本项目的实施为间歇性禁食改善糖代谢提供新的理论依据，同时也为肥胖和2型糖尿病的临床治疗提供新的思路和方法。