Energy Balance in the Obese CCK-A Receptor Deficient Rat

描述（由申请人提供）：肥胖在美国已达到流行病的比例，并且在人类研究和动物模型中已经确定了遗传和环境对肥胖的发展和维持的贡献。遗传性肥胖的啮齿动物模型的分析已经阐明了与代谢和能量平衡的总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。缺乏CCK 1受体的肥胖大冢长-埃文斯德岛脂肪（OLETF）大鼠是一种独特的肥胖遗传模型，因为它似乎在对食物摄入的膳食内控制至关重要的外周肠-脑肽信号传导途径和不依赖于瘦素的下丘脑信号传导途径两者中均存在缺陷。OLETF大鼠是肥胖和贪食的，我们已经表明，它们的贪食，其特点是增加膳食的大小，占肥胖。第一个具体目标下的实验将描述迷走神经和背内侧下丘脑（DMH）CCK-A受体在紊乱的膳食模式和整体hyperpagia的贡献，并评估DMH的神经肽Y过表达在其hyperphagia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大鼠的食物摄入和体重正常化。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）在介导运动效应中的作用，并使用微阵列技术试图确定有助于运动短期和长期效应的新因素。第三个具体目标下的实验将研究母亲的影响在食欲过盛和肥胖症的发展中的作用。初步结果表明，将对照Long Evans德岛大冢（LETO）幼仔与OLETF母仔交叉饲养导致雄性后代肥胖。拟议的实验将从所涉及的母体因素以及这种经验如何改变发育中的幼崽大脑中的连接模式和基因表达的角度来研究这种现象的基础。总之，这些研究的结果将：1）表征OLETF大鼠中摄食过多和肥胖的潜在机制，2）确定改变外周饱腹感和下丘脑信号传导紊乱的影响的运动诱导因素，以及3）确定可能偏向肥胖的发育影响。

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.