Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet
Targeted ablation of glucose-dependent insulinotropic polypeptide-producing cells in transgenic mice reduces obesity and insulin resistance induced by a high fat diet
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DOI：
10.1074/jbc.m710466200
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发表时间：
2008-06-27
影响因子：
4.8
通讯作者：
Wice, Burton M.
中科院分区：
文献类型：
--
作者：
Althage, Matthew C.;Ford, Eric L.;Wice, Burton M.
K细胞是位于小肠近端肠内分泌细胞的一种特殊亚型，可产生葡萄糖依赖型胰岛素多肽（GIP）、xenin和其他潜在的未知激素。由于GIP促进体重增加和胰岛素抵抗，减少K细胞的激素释放可能导致体重减轻和胰岛素敏感性增加。然而，协调降低所有K细胞衍生激素循环水平的后果尚不清楚。为了减少功能K细胞的数量，利用大鼠GIP启动子/基因的调控元件在转基因小鼠中表达减毒白喉毒素A链。在GIP/DT转基因小鼠中，K细胞数量、GIP转录物和血浆GIP水平均显著降低。其他肠内分泌细胞类型未消融。对照组和以标准食物喂养的GIP/DT小鼠的食物摄入量、体重和血糖水平对胰岛素或腹腔内葡萄糖的反应相似。与单或双肠促胰岛素受体敲除小鼠相比，在GIP/DT动物中没有肠促胰岛素反应，这表明K细胞产生GIP和额外的肠促胰岛素激素。高脂喂养21-35周后，GIP/DT小鼠的肠促胰岛素反应部分恢复。与野生型小鼠相比，转基因小鼠的体重（25%）、血浆瘦素水平（77%）、每日食物摄入量（16%）、能量消耗（10%）和胰岛素敏感性均显著降低。无论饮食如何，转基因动物的长期葡萄糖稳态没有受到严重干扰。综上所述，在GIP/DT小鼠中进行的研究表明，K细胞在调节体重和胰岛素敏感性方面发挥了重要作用。
The K cell is a specific sub-type of enteroendocrine cell located in the proximal small intestine that produces glucose-dependent insulinotropic polypeptide (GIP), xenin, and potentially other unknown hormones. Because GIP promotes weight gain and insulin resistance, reducing hormone release from K cells could lead to weight loss and increased insulin sensitivity. However, the consequences of coordinately reducing circulating levels of all K cell-derived hormones are unknown. To reduce the number of functioning K cells, regulatory elements from the rat GIP promoter/gene were used to express an attenuated diphtheria toxin A chain in transgenic mice. K cell number, GIP transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT transgenic mice. Other enteroendocrine cell types were not ablated. Food intake, body weight, and blood glucose levels in response to insulin or intraperitoneal glucose were similar in control and GIP/DT mice fed standard chow. In contrast to single or double incretin receptor knock-out mice, the incretin response was absent in GIP/DT animals suggesting K cells produce GIP plus an additional incretin hormone. Following high fat feeding for 21-35 weeks, the incretin response was partially restored in GIP/DT mice. Transgenic versus wildtype mice demonstrated significantly reduced body weight (25%), plasma leptin levels (77%), and daily food intake (16%) plus enhanced energy expenditure (10%) and insulin sensitivity. Regardless of diet, long term glucose homeostasis was not grossly perturbed in the transgenic animals. In conclusion, studies using GIP/DT mice demonstrate an important role for K cells in the regulation of body weight and insulin sensitivity.