Programmed adiposity: genetic in utero and postnatal determinants

描述(由申请人提供)：早期的营养环境被假设为“规划”成人暴食、肥胖和相关的医疗并发症的风险。然而，由于缺乏合适的模型，区分遗传、宫内和出生后的影响一直受到阻碍。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”影响与基因组和出生前的影响分开。在具体目标1中，将研究肥胖水坝养育导致终生吞噬症的行为和神经化学机制。实验将确定吞噬过多的个体发生；过量摄入的行为学基础，以及功能神经适应在相互关联的系统中的中介作用，这些系统包括神经肽Y1、u/kappa阿片和大麻素1型受体系统，这些系统被认为是暴饮暴食的基础，具有增加的正向驱动而不是减少的负反馈。这些研究结合了以下特点：1)行为的高度创新的微结构分析，2)强大的同胞分离-收养研究设计，3)用新的、高度选择性的药物配体进行详细的剂量-反应分析，4)最近开发的肥胖风险的多基因模型，5)增强食品功效的工具措施，以及6)匹配良好的受控饮食暴露。此外，出生前或出生后营养因素发育过程中调节成人食欲神经回路的荷尔蒙和近端分子脑机制还不是很清楚。因此，特定的目标2将确定出生后营养对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，这些因素被假设为肥胖对食欲的长期影响。激光捕获显微切割离散的下丘脑核团将与微阵列分析相结合，以识别新生儿之间差异表达的基因，这些基因与这些“编程”荷尔蒙的出生后偏差有关。微阵列分析还将用于识别出生时在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不同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，这些荷尔蒙或下丘脑基因可以控制发育过度的动物的终生吞噬，以及在成年后直接调节暴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.