Disruption of CCCK-A receptor gene and obesity, diabetes mellitus, and abnormal behavior

我们发现，OLETF大鼠，一个近交系的自发突变，发展持续高血糖和轻度肥胖，不表达CCK-A受体基因，因为遗传异常。大鼠CCK-A受体基因长约10 kb，由5个外显子和4个内含子组成，在OLETF大鼠中缺失2个外显子。OLETF大鼠表现出几种可能由于CCK-A受体缺陷导致的功能异常，包括摄食过多、探索行为减少、胰岛素和胰酶分泌反应受损以及胰腺生长和再生迟缓。在本研究中，我们发现了额外的观察结果。OLETF大鼠24周龄后能量消耗的昼夜节律变平。18周龄时，脂质从小肠粘膜向淋巴液的转运增强，通过预防肥胖，这种增强得到改善。限制应激后淋巴细胞亚群无明显变化。微量分析表明，纹状体多巴胺的释放与对照组LETO大鼠无差异。两种品系的PET纹状体成像也相当。以确定CCK-A受体基因敲除小鼠的作用。小鼠具有生育能力，并显示正常生长。在4只CCK-A受体（-/-）小鼠中，有3只在65周龄时观察到胆结石形成，而在（+/-）和（+/+）小鼠中未观察到胆结石形成。

We found that OLETF rats, an inbred strain of spontaneous mutants, which develop persistent hyperglycemia and mild obesity, did not express CCK-A receptor gene because of a genetic abnormality. The rat CCK-A receptor gene is -10kb long and consists of five exons interrupted by four introns, and two exons are deleted in OLETF rats. OLETF rats revealed several abnormal functions possible due to a defect of the CCK-A receptor including hyperphagia, decrease in exploratory behavior, impaired response of insulin and pancreatic enzyme secretion, and retardation of pancreatic growth and regeneration. In the present study, we found additional observations. The diurnal rhythm of energy expenditure was flattened after 24 weeks of age in OLETF rats. The transport of lipid from the small intestinal mucosa into the lymph was enhanced at 18 weeks of age and this enhancement was improved by the prevention of obesity. The lymphocyte subpolulation after restriction stress was not changed. The dopamine release from the striatum was not different from the control LETO rats by microanalysis. The imaging of striatum by PET was also comparable for both strains. In order to determine the role of CCK-A receptor gene knockout mice. The mice are fertile and show normal growth. Gallstone formation was observed at 65 weeks of age in 3 of 4 CCK-A receptor (-/-) mice, whereas no gallstone formation was observed in (+/-) and (+/+) mice.