Abstract：
Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin (NEPfl/fl) mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in high-fat-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.
摘要：
Neprilysin是一种普遍存在的肽酶，可以通过切割促胰岛素肽来调节葡萄糖稳态。虽然Neprilysin的整体缺失可以保护小鼠免受高脂饮食（HFD）诱导的胰岛素分泌功能障碍，以组织特异性方式消融脑啡肽的策略有利于限制脱靶效应。因为促胰岛素肽是在肠道中产生的，我们试图确定在饲喂HFD的小鼠中,肠道特异性脑啡肽酶缺失是否对胰岛素分泌产生类似于全局脑啡肽酶缺失的有益作用.通过使Vil-Cre和Floxed脑啡肽酶(NEPfl/fl)小鼠交叉产生肠细胞中脑啡肽酶条件性缺失(NEPGut-/-)的小鼠。Neprilysin活性在NepGut-/-小鼠的整个肠道中几乎被废除，在血浆中相似，NEPGut-/-与对照小鼠的胰腺和肾脏。在基线和HFD喂养14周后进行口服葡萄糖耐量试验，在此期间评估葡萄糖耐量和葡萄糖刺激的胰岛素分泌(GSIS).尽管14周时体重增加相似，NEPGut-/-显示较低的空腹血糖水平，与对照小鼠相比，葡萄糖耐量提高，GSIS增加。总之,肠道特异性脑啡肽缺失概括了在高脂喂养小鼠中整体脑啡肽缺失所观察到的增强的GSIS。因此，特别是在肠道中抑制脑啡肽酶的策略可以防止脂肪诱导的葡萄糖耐受不良和β细胞功能障碍。
