Programmed adiposity: genetic in utero and postnatal determinants

描述（由申请人提供）：早期营养环境被假设为“程序”成人暴饮暴食，肥胖症和相关的医疗并发症的风险。然而，由于缺乏适当的模型，区分遗传、宫内和产后效应受到阻碍。目前的应用使用了一种新的啮齿动物模型，该模型将出生后早期生活对食欲的“印记”效应与基因组和产前效应分开。在具体目标1中，将研究肥胖母鼠饲养导致终生摄食过多的行为和神经化学机制。实验将确定暴食症的个体发生;过量摄入的行为基础，增加的正驱动而不是减少的负反馈假设为暴饮暴食的基础;以及功能性神经适应在相互关联的系统中的介导作用，这些系统有助于喂养的“正驱动”控制，即神经肽Y1，mu/kappa阿片样物质和大麻素1型受体系统。这些研究联合收割机了以下特征：1）行为的高度创新的微观结构分析，2）强大的同胞配对分开采用研究设计，3）使用新型、高度选择性药理学配体的详细剂量反应分析，4）最近开发的肥胖风险多基因模型，5）食物强化功效的仪器测量，以及6）匹配良好的受控饮食暴露。此外，激素和近端分子大脑机制，产前或产后营养因素发育程序成人食欲神经回路还没有很好地理解。因此，具体目标2将确定产后营养对3种体液因子-瘦素、脂联素或皮质酮-的早期个体发育的影响，这些体液因子被假设为肥胖收养对食欲的长期影响。离散下丘脑核的激光捕获显微切割将与微阵列分析相结合，以确定新生儿之间差异表达的基因，这些基因与这些“编程”激素的出生后偏差有关。微阵列分析还将用于鉴定出生时弓状核中差异表达的基因，这些基因与成年后暴饮暴食和肥胖的差异遗传或宫内营养过剩风险有关。这些结果可能会确定激素或下丘脑基因，这些基因在发育过度营养的动物中编程终身暴食，以及在成年期促进过度饮食的行为和神经化学机制。

DESCRIPTION (provided by applicant): Early nutritional environment is hypothesized to "program" adult risk for overeating, adiposity, and associated medical complication. However, distinguishing genetic, intrauterine, and postnatal effects has been hampered by the lack of appropriate models. The current application uses a new rodent model that separates "imprinting" effects of early postnatal life on appetite, from genomic and prenatal effects. In Specific Aim 1, behavioral and neurochemical mechanisms by which being reared by an obese dam results in life-long hyperphagia will be studied. Experiments will determine the ontogeny of hyperphagia; the behavioral basis of excess intake, with increased positive drive rather than diminished negative feedback hypothesized to underlies the overeating; and the mediating role of functional neuroadaptations in interrelated systems that subserve the "positive drive" control of feeding, namely neuropeptide Y1, mu/kappa opioid and cannabinoid type 1 receptor systems. The studies combine the following features: 1) highly innovative microstructure analysis of behavior, 2) powerful sibpair split-adoption research designs, 3) detailed dose-response analysis with novel, highly selective pharmacological ligands, 4) recently developed polygenic models of obesity risk, 5) instrumental measures of the reinforcing efficacy of food, and 6) well- matched, controlled diet exposure. In addition, the hormonal and proximate molecular brain mechanisms by which prenatal or postnatal nutritional factors developmentally program adult appetite neurocircuitry are not well understood. Therefore, Specific Aim 2 will determine the effects of postnatal nutrition on early ontogeny of 3 humoral factors - leptin, adiponectin, or corticosterone - hypothesized to program long-term effects of obese adoption on appetite. Laser capture microdissection of discrete hypothalamic nuclei will be combined with microarray analysis to identify genes that are differentially expressed between neonates in relation to postnatal deviations in these "programming" hormones. Microarray analysis also will be used to identify genes that are differentially expressed at birth in the arcuate nucleus in relation to differential genetic or intrauterine overnutrition risk for overeating and obesity in adulthood. The results may identify hormones or hypothalamic genes that program lifelong hyperphagia in developmentally overnourished animals as well as the behavioral and neurochemical mechanisms that proximately mediate the overeating in adulthood.