肠上皮胰岛素信号在全身葡萄糖及脂质平衡中发挥重要作用

小肠上皮作为一种专业分化的上皮，有防止微生物侵袭的屏障和促进营养成分的吸收两种功能。小肠上皮细胞表面遍布胰岛素受体，但是其在这种特异细胞上的作用还没有被完全了解。

 

许多研究显示小肠胰岛素信号在葡萄糖吸收中起作用，其他研究则推断其在抑制乳糜微粒，从而在全身脂质稳态的调节中起作用。

 

为了搞清小肠上皮细胞中胰岛素信号的作用。我们通过杂交C57BL/6 胰岛素受体floxed小鼠和VILIRKO小鼠制造了小肠上皮细胞中胰岛素受体缺失的小鼠。VILIRKO小鼠中，能够进行正常孟德尔比率生产的小鼠是可育的，并显示按照正常饮食喂养没有明显的生长或者代谢异常。

 

为了进行对照，我们喂养了一组高脂肪饮食VILIRKO小鼠，同窝对照相比显示体重下降(53.5 ± 1.3g vs. 44.4 ± 3.9g)和口服葡糖糖耐受的上升。VILIRKO小鼠还显示出明显减少的脂肪肝的减少。这一结果和血清甘油三酸酯水平的下降是同步的，胆固醇水平也出现了同样的趋势。有意思的是，VILIRKO小鼠内脏脂肪增加，但是皮下的脂肪组织减少。在循环中的抵抗素水平增加当时其瘦素水平保持不变。

 

这些数据显示小肠内皮胰岛素信号在管理全身的胰岛素代谢敏感性和脂肪分布中起到重要的作用，它可以成为一个脂质代谢管理中重要的外部管理因子。

 

The intestinal mucosa has a dual function in providing a specialized epithelium as a barrier to prevent microbial invasion and to facilitate absorption of nutrients. The insulin receptor is expressed throughout the cell surface of intestinal epithelial cells but its function in these specific cells is not fully understood. Some studies indicate a role for intestinal insulin signaling in glucose absorption while others suggest a role in the suppression of chylomicrons and thereby the modulation of whole body lipid homeostasis. To dissect the role of insulin signaling in the intestinal epithelium we generated mice lacking the insulin receptor specifically in the intestinal epithelium by crossing C57BL/6 insulin receptor floxed mice with mice expressing cre-recombinase under the villin promoter (VILIRKO). VILIRKO mice were born in a normal Mendelian ratio were fertile and showed no obvious developmental or metabolic abnormalities on a chow diet. In contrast when fed a high fat diet VILIRKO mice exhibited reduced body weight (53.5 ± 1.3g vs. 44.4 ± 3.9g) and improved oral glucose tolerance when compared to control littermates. In addition VILIRKO mice showed strongly reduced hepatic steatosis. This was accompanied by reduced serum triglyceride levels as well as a trend to reduced cholesterol levels. Interestingly VILIRKO mice had increased visceral but not subcutaneous adipose tissue. Circulating resistin levels were also increased whereas circulating leptin levels remained unchanged. These data indicate that intestinal epithelial insulin signaling has an important role in the regulation of whole body metabolism insulin sensitivity and fat distribution and could be an important extrinsic regulator of hepatic lipid metabolism.