Involvement of cholecystokinin 2 receptor in food intake regulation:: Hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice
Involvement of cholecystokinin 2 receptor in food intake regulation:: Hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice
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DOI：
10.1210/en.2006-1064
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发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Dufresne, Marlene
中科院分区：
文献类型：
--
作者：
Clerc, Pascal;Constans, Maria Gracia Coll;Dufresne, Marlene
胆囊收缩素（CCK）作为饱腹感因子的作用已被广泛记载。虽然大多数研究表明CCK1受体介导了食物摄入的控制，但不能完全排除CCK2受体（CCK2R）在cck诱导的饱腹感中的作用。我们在CCK2R（-/-）小鼠中验证了CCK2R失能破坏调节通路并影响摄食行为的假设。CCK2R（-/-）小鼠出现与贪食相关的肥胖。肥胖与脂肪细胞肥大引起的脂肪沉积增加有关。几种脂肪因子的表达失调与肥胖一致。此外，CCK2R（-/-）小鼠的空腹血糖和胰岛素血症升高、葡萄糖耐量受损和肝脏胰岛素抵抗显示，肥胖与葡萄糖稳态紊乱有关。体外分离脂肪细胞代谢分析与储存保存的胰岛素敏感性增加一致。在对照小鼠脑室内注射胃泌素后，抑制进食并同时增加下丘脑原黑素皮质素的表达，表明下丘脑CCK2受体介导了食物摄入的抑制。通过对敲除小鼠和对照组下丘脑调节基因表达的比较分析，发现CCK2R（-/-）小鼠中ghrelin受体过表达，表明促食途径上调。在体重正常化后也观察到这种效应，表明CCK2R（-/-）小鼠贪食和肥胖的发生具有致病作用。我们的研究结果证明，CCK2受体活性在控制食物摄入中起着重要的调节作用。
The role of cholecystokinin (CCK) as a satiety factor has been extensively documented. Although most work implies that CCK1 receptor mediates the control of food intake, a contributing role for CCK2 receptor (CCK2R) in the CCK-induced satiety cannot be totally excluded. The hypothesis that CCK2R invalidation disrupts regulatory pathways with impact on feeding behavior was examined in CCK2R(-/-) mice. CCK2R(-/-) mice developed obesity that was associated with hyperphagia. Obesity was related with increased fat deposition resulting from adipocyte hypertrophy. Expression of several adipokines was dysregulated consistently with obesity. Moreover, obesity was associated with disturbed glucose homeostasis as revealed by increased fasting glycemia and insulinemia, impaired glucose tolerance, and hepatic insulin resistance in CCK2R(-/-) mice. In vitro analysis of isolated adipocytes metabolism was consistent with increased storage preserved insulin sensitivity. Suppression of feeding and concomitant increased expression of hypothalamic proopiomelanocortin after intracerebroventricular injection of gastrin into control mice demonstrates that hypothalamic CCK2 receptors mediate inhibition of food intake. Comparative analysis of hypothalamic mediator gene expression in fed knockout and control mice demonstrated overexpression of ghrelin receptors in CCK2R(-/-) mice, indicating up-regulation of orexigenic pathways. This effect was also observed after body weight normalization, indicating a causative role in the development of hyperphagia and obesity of CCK2R(-/-) mice. Our results give evidence that CCK2 receptor activity plays a contributing regulatory role in the control of food intake.