Epigenetic mechanisms in obesity

描述(由申请人提供)：近几十年来，美国和其他发达国家的肥胖率急剧上升。这一趋势正在影响各个年龄段的人，包括育龄妇女。一个主要的担忧是，孕妇在怀孕期间肥胖可能会改变宫内环境，从而使其后代永久肥胖。存活的黄色刺鼠(Avy)是探索母体肥胖和饮食对子代体重影响的理想模型。Avy/a小鼠自发性充血，并发展成成人肥胖症。然而，肥胖的严重程度在等位基因的Avy/a小鼠中差异很大。这项研究的总体假设是，怀孕和/或哺乳期间的母亲肥胖会影响发育中的下丘脑中基因特异性DNA甲基化模式的建立，导致下丘脑基因表达、食物摄入量调节和体重的永久性变化。该项目的具体目标是：1)表征影响摄食调节的下丘脑基因的发育建立和组织特异性；2)在Avy小鼠模型中，确定母体肥胖对子代体重的影响是否发生在产前或出生后早期；以及3)确定成年Avy/a小鼠下丘脑中特定基因的甲基化和表达是否与肥胖相关。这项动物模型研究对于阐明母体肥胖影响子代体重的机制是必要的；这些信息将使我们能够准确地评估这种现象对人类肥胖病因的影响，并潜在地设计有效的干预措施。公共卫生相关性：拟议研究的总体假设是，孕期和/或哺乳期的母亲肥胖会影响发育中的下丘脑中特定基因DNA甲基化模式的建立，导致下丘脑基因表达、食物摄入量调节和体重的永久性变化。我们将在有和没有肥胖遗传倾向的小鼠身上研究这一假说。我们的结果将阐明母亲肥胖影响后代体重的机制，使我们能够准确地评估这种现象对人类肥胖病因的影响，并最终设计有效的干预措施。

DESCRIPTION (provided by applicant): Obesity prevalence in the US and other developed countries has increased dramatically in recent decades. This trend is affecting individuals at every age, including women of child- bearing age. A major concern is that maternal obesity during pregnancy may alter the intrauterine environmental and thereby perpetuate obesity in her offspring. The viable yellow agouti (Avy) mouse is an ideal model in which to explore the effects of maternal obesity and diet on offspring body weight. Avy/a mice are spontaneously hyperphagic and develop adult-onset obesity. Severity of obesity, however, is highly variable among isogenic Avy/a mice. The overall hypothesis of the proposed research is that maternal obesity during pregnancy and/or lactation affects the establishment of gene-specific DNA methylation patterns in the developing hypothalamus, causing permanent changes in hypothalamic gene expression, food intake regulation, and body weight. The specific aims of this project are to: 1) characterize the developmental establishment and tissue-specificity of DNA methylation at hypothalamic genes that affect food intake regulation, 2) in the Avy mouse model, determine if the effects of maternal obesity on offspring body weight occur during prenatal or early postnatal development, and 3) determine if methylation and expression of specific genes in the hypothalamus of adult Avy/a mice are correlated with obesity. This research in animal models is necessary to elucidate the mechanisms by which maternal obesity affects offspring body weight; this information will enable us to accurately gauge the impact of such phenomena on the etiology of human obesity and potentially design effective interventions. PUBLIC HEALTH RELEVANCE: The overall hypothesis of the proposed research is that maternal obesity during pregnancy and/or lactation affects the establishment of gene-specific DNA methylation patterns in the developing hypothalamus, causing permanent changes in hypothalamic gene expression, food intake regulation, and body weight. We will investigate this hypothesis in mice with and without a genetic predisposition to obesity. Our results will elucidate the mechanisms by which maternal obesity affects offspring body weight, enabling us to accurately gauge the impact of such phenomena on the etiology of human obesity and, eventually, design effective interventions.