胰岛素诱导的巨噬细胞糖原代谢在肥胖引起的慢性炎症中的作用研究

Obesity is associated with chronic inflammation in tissues such as adipose tissue and bowel, which may be the precipitating factor for many of its associated complications such as insulin resistance and cancer. The research indicates that macrophages play an important role in the inflammation caused by obesity. In a previous study, we found that high insulin levels in obese individuals promote glycogen synthesis in macrophages, and glucose-6-phosphate produced by glycogenolysis flow to the pentose phosphate pathway. Inhibited glycogenolysis and the flow of pentose phosphate pathway would affect the redox and cell survival. Thus we hypothesized that under the influence of insulin, macrophages altering the metabolism level and providing NADPH via pentose phosphate pathway to maintain GSH levels and the secretion of cytokines, resulting in tissue inflammation. This project will further elucidate the mechanism of macrophages activation and chronic inflammation induced by high insulin level in obese individuals, providing a new direction and theoretical basis for inhibiting the occurrence of chronic inflammation caused by obesity.

肥胖与脂肪和肠道等组织的慢性炎症有关，而肥胖引起的炎症也与胰岛素抵抗、癌症的发生密切相关。研究表明，巨噬细胞在肥胖引起的炎症中起着十分重要的作用。申请人在前期研究中发现，肥胖个体体内的高胰岛素水平会促进巨噬细胞胞内糖原的合成，过量的糖原分解产生的6-磷酸葡萄糖可以流向磷酸戊糖代谢途径，抑制糖原分解及磷酸戊糖代谢途径会影响细胞的氧化还原平衡和存活。因而我们假设，在胰岛素的作用下，巨噬细胞上调糖原代谢水平，通过磷酸戊糖代谢提供NADPH以维持GSH水平，从而维持自身的存活并保证了炎症细胞因子的分泌，引起组织炎症。本项目将进一步阐明肥胖机体高胰岛素水平引起巨噬细胞活化，造成组织慢性炎症过程中巨噬细胞代谢的变化，为以巨噬细胞等免疫细胞为靶点，抑制肥胖个体组织炎症的发生提供新方向和理论基础。

肥胖与肠道组织的慢性炎症密切相关，巨噬细胞在肥胖引起的炎症中起着十分重要的作用。阐明糖代谢如何通过巨噬细胞促进肠道炎症、探索肥胖引起肠道炎症的机制，能为靶向巨噬细胞抑制肥胖造成的肠道炎症提供理论基础。在本项目的资助下，我们发现肥胖小鼠肠道组织中的巨噬细胞浸润增加，且肠道组织产生胰岛素抵抗现象，而巨噬细胞中增强的糖原-磷酸戊糖代谢途径通过维持巨噬细胞的氧化还原平衡促进肠道炎症。另外，鉴于糖代谢在巨噬细胞极化过程中的重要性，我们研究发现，高糖饮食能够通过激活巨噬细胞中ROS介导的NF-kB信号通路促进小鼠的肠道炎症，作为ROS的清除剂，N-乙酰半胱氨酸能够抑制高糖加剧的的小鼠肠道炎症。我们还发现，肥胖小鼠的肠道炎症还与肥胖造成的高血糖密切相关，肥胖小鼠体内较高的血糖水平能够抑制肠上皮细胞中BCAT2的表达，造成肠道组织中支链氨基酸的积累，造成肠道炎症。以上结果说明，肥胖能够通过改变巨噬细胞中糖代谢水平或者上皮细胞中支链氨基酸代谢水平，从而促进肠道炎症。