Energy Balance in the Obese CCK-A Receptor Deficient Rat

描述(申请人提供)：肥胖症在美国已经达到流行的程度，在人类研究和动物模型中，已经确定了遗传和环境因素对肥胖症的发展和维持的影响。对遗传性肥胖的啮齿动物模型的分析已经阐明了与新陈代谢和能量平衡的整体控制相关的下丘脑信号通路。其中大多数涉及瘦素信号通路方面的缺陷。肥胖的OLETF大鼠缺乏CCK1受体，是肥胖的一种独特的遗传模型，因为它似乎在对食物摄入量的控制至关重要的外周肠脑多肽信号通路和下丘脑独立于瘦素的信号通路中都存在缺陷。OLETF大鼠是肥胖和吞噬过度的，我们已经证明，它们的吞噬功能亢进，以食物体积增加为特征，是肥胖的原因。在第一个特定目标下的实验将表征迷走神经和下丘脑背侧内侧(DMH)CCK-A受体在进食模式紊乱和整体肥大中的作用，并评价DMH过表达NPY在其吞噬功能亢进中的作用。在第二个具体目标中，我们将继续我们的研究，证明运动能够使OLETF大鼠的摄食量和体重正常化。这些实验将评估运动和饮食之间的相互作用，评估DMH促肾上腺皮质激素释放肽(CRF)在调节运动效果中的作用，并使用微阵列技术试图确定有助于运动短期和长期效果的新因素。第三个特定目标下的实验将检验母亲的影响在过度吞噬和肥胖发展中的作用。初步结果表明，将长伊万德岛大冢(Long Evans Tokushima Otsuka(Leto))幼崽交叉饲养到OLETF水坝会导致雄性后代肥胖。拟议中的实验将从母体因素的角度，以及这种经历如何改变发育中的幼崽大脑中的连接和基因表达模式，来研究这种现象的基础。总之，这些研究的结果将：1)表征OLETF大鼠过度吞噬和肥胖的机制，2)确定运动诱导的因素，改变紊乱的外周饱腹感和下丘脑信号的影响，3)确定可能倾向于肥胖的发育影响。

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the United States, and both genetic and environmental contributions to the development and maintenance of obesity have been identified in human studies and animal models. Analyses of rodent models of genetic obesity have illuminated hypothalamic signaling pathways related to the overall control of metabolism and energy balance. The majority of these have involved deficits in aspects of the leptin signaling pathway. The obese Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking CCK1 receptors is a unique genetic model of obesity in that it appears to have deficits in both a peripheral gut-brain peptide signaling pathway critical to the within meal control of food intake and in hypothalamic signaling pathways that are independent of leptin. OLETF rats are obese and hyperphagic, and we have shown that their hyperphagia, characterized by increased meal size, accounts for the obesity. Experiments under the first specific aim will characterize the contributions of vagal and dorsal medial hypothalamic (DMH) CCK-A receptors in the disordered meal patterns and overall hyperpagia and evaluate the role of DMH overexpression of NPY in their hyperphagia. In the second specific aim, we will follow up on our studies demonstrating the ability of exercise to normalize food intake and body weight in OLETF rats. These experiments will assess interactions between exercise and diet, assess a role for DMH corticotrophin releasing peptide (CRF) in mediating the effects of exercise and use microarracy techniques in an attempt to identify novel factors that contribute to both the short and long term effects of exercise. Experiments under the third specific aim will examine the role of maternal influences in the development of hyperphagia and obesity. Preliminary results demonstrate that cross fostering control Long Evans Tokushima Otsuka (LETO) pups to OLETF dams results in obesity in male offspring. Proposed experiments will investigate the basis of this phenomenon both from the standpoint of the maternal factors involved and how that experience modifies patterns of connectivity and gene expression in the brains of the developing pups. Together, results from these studies will: 1) characterize the mechanisms underlying the hyperphagia and obesity in OLETF rats, 2) identify exercise induced factors that modify the effects of disordered peripheral satiety and hypothalamic signaling, and 3) identify developmental influences that may bias towards obesity.