应激通过瘦素调节肠道通透性在肥胖发病中的机制研究

Chronic stress can lead to obesity. Chronic stress state has elevated intestinal permeability (IP) and induces endotoxin translocation, which may be an important link leading to obesity. Our previous study found that leptin can improve intestinal epithelial cell proliferation/apoptosis imbalance, and up-regulate the expression of intestinal tight junction proteins, thereby reducing the increase of IP in the systemic inflammatory state and reducing circulating endotoxin levels. However, the effect of leptin on IP under chronic stress is still lacking in related research at home and abroad. This project intends to establish a chronic stress model using C57BL/6J wild-type and leptin-deficient mice, to discuss the effect of leptin on IP under chronic stress, and to identify the leptin-JAK2/STAT3 signaling pathway to IP by cell experiments. This project will clarify the role of leptin on IP under chronic stress and its mechanisms, and provide a theoretical basis for the treatment of stress-related obesity.

慢性应激可导致肥胖发生。慢性应激状态存在肠道通透性（IP）升高并诱发内毒素易位，可能为导致肥胖发生的重要环节。我们前期研究发现，瘦素能够通过改善肠上皮细胞增殖/凋亡失衡，上调肠上皮细胞间紧密连接蛋白表达，从而减轻动物全身炎症状态下IP的升高，降低循环内毒素水平。然而瘦素对于应激状态下IP的影响目前国内外尚缺乏相关研究。本项目拟采用C57BL/6J野生型及瘦素缺陷小鼠建立慢性应激模型，讨论瘦素对慢性应激状态下IP的影响，同时通过细胞实验明确瘦素-JAK2/STAT3信号通路对IP的调控作用。本项目将阐明瘦素对慢性应激状态下IP的作用以及机制途径，为应激相关肥胖的治疗新靶点提供理论依据。

背景：慢性应激状态可导致肥胖发生，亦可造成肠道通透性变化。慢性应激引起肠上皮屏障改变与代谢的变化尚待研究，瘦素可能参与其中作用。.方法：16只雄性C57BL/6J小鼠随机分配于社交失败模型组（S）及对照组（C），每日测量动物体重。造模21天后检测动物糖耐量，检测肠道FD4吸收水平，观察空肠病理结构，采用免疫印迹法检测肠道紧密连接蛋白occludin、claudin-1、瘦素及其受体表达水平。.结果：慢性应激模型建立成功。模型组小鼠体重及空腹血糖高于对照组（p<0.05）。应激组小鼠肠道FD4吸收较对照组增加（C 5.15±0.39mmol/L vs. S 7.46±0.62mmol/L, p=0.035），肠上皮绒毛高度下降（p<0.05）。模型组动物肠道occludin（C 0.86±0.07 vs. S 0.64±0.05, p=0.022）、claudin-1（C 0.97±0.05 vs. S 0.83±0.03, p=0.018）的表达水平均低于对照组。造模后小鼠肠上皮瘦素水平下降（C 1.53±0.16 vs. S 0.96±0.16, p=0.044），瘦素受体表达无明显变化。.结论：慢性应激状态可引起肠道瘦素水平下降，肠上皮屏障损伤并造成肠道通透性增加。这可能导致了应激状态下肥胖及糖代谢异常的发生。