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

我们发现OLETF大鼠，一种自发突变的近交系，会出现持续性高血糖和轻度肥胖，由于遗传异常而不表达CCK-A受体基因。大鼠CCK-A受体基因长-10kb，由5个被4个内含子打断的外显子组成，在OLETF大鼠中有2个外显子缺失。由于CCK-A受体的缺陷，OLETF大鼠出现了多种可能的功能异常，包括贪食、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。在目前的研究中，我们发现了额外的观察结果。24周龄后，OLETF大鼠的能量消耗昼夜节律趋于平缓。18周龄时，脂质从小肠粘膜转运到淋巴的能力增强，这种增强通过预防肥胖得到改善。限制应激后淋巴细胞亚群无明显变化。经微量分析，纹状体多巴胺释放量与LETO对照组无明显差异。两株的纹状体PET成像也具有可比性。以确定敲除小鼠CCK-A受体基因的作用。这些老鼠是可生育的，生长正常。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（+/-）和（+/+）小鼠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.