Maternal Obesity: A Sheep Model

描述（由申请人提供）：对于小胎龄（SGA）和大胎龄（LGA）新生儿，出生体重与日后发生冠心病的风险之间存在相关性。然而，大多数临床和基础科学研究都集中在低出生体重的影响上。母亲肥胖和妊娠期糖尿病是LGA新生儿的主要决定因素。在这些条件下，产妇肥胖作为一个潜在的产前损伤，导致胎儿编程很少受到关注。该提案的目标是开发母体肥胖的动物模型，其将允许研究胎儿对母体肥胖和/或出生LGA的适应性增加发展心血管疾病的风险的机制。我们的总体假设是，肥胖母亲的后代脂肪组织有永久性改变，使他们容易发展异常的内皮功能/血管反应性和高血压，并在成年生活。因此，我们建议：1）肥胖孕妇的母体环境影响了胎儿的适应性，对后代的脂肪组织调节和功能有长期影响; 2）肥胖母亲后代的脂肪组织在激素（脂联素、瘦素、β-内酰胺酶）和细胞因子（TNF？，IL-6和CRP）产生和分泌;3）脂肪组织产生和/或激素和细胞因子分泌的改变在血管反应性异常和高血压的发展中起核心作用。我们将测试这些假设与以下具体目标：具体目标1：建立一个动物模型的母亲肥胖（过度喂养）的绵羊喂养一个完全平衡的饮食。具体目标2：确定肥胖绵羊的后代是否发生内皮功能/血管反应性和/或高血压的改变。具体目标3：确定肥胖绵羊的后代是否表现出胰岛素抵抗以及脂肪组织激素和细胞因子表达和分泌的改变。公共卫生相关性：我们的建议将提供一个机会，在动物模型中，已经知道很多关于脂肪细胞的功能，并在出生前和出生后的内分泌环境是类似于人类婴儿的母亲肥胖的影响进行研究。我们的建议的独特之处之一是研究孕产妇肥胖作为一个孕前/妊娠连续体，最常见的临床表现的孕产妇肥胖。收集的数据将作为新应用程序（R 01）的基础，旨在识别后代中存在的异常的潜在机制。未来的实验将在不同的发育阶段进行，以确定肥胖增加的任何有害影响的纵向性质。

DESCRIPTION (provided by applicant: An association between birthweight and later risk for developing coronary heart disease has been shown for both small (SGA) and large (LGA) for gestational age newborns. However, most clinical and basic sciences studies have concentrated on effects of low birthweight. Maternal obesity and gestational diabetes (GDM) are the main determinants of LGA newborns. Of these conditions, maternal obesity has received little attention as a potential prenatal insult leading to fetal programming. The goal of this proposal is to develop an animal model of maternal obesity that will allow study of the mechanisms by which fetal adaptations to maternal obesity and/or being born LGA increase the risk for developing cardiovascular diseases. Our global hypothesis is that the offspring of obese mothers have permanent alterations in adipose tissue that predispose them to develop abnormalities in endothelial function/vascular reactivity and hypertension and in adult life. Therefore, we propose that: 1) The maternal environment of the obese pregnant female elicits fetal adaptations which have long-term effects on the offspring's adipose tissue regulation and function; 2) The adipose tissue in the offspring of obese mothers has alterations in hormonal (adiponectin, leptin, resistin) and cytokine (TNF?, IL-6 and CRP) production and secretion;3) Alterations in adipose tissue production and/or secretion of hormones and cytokines play a central role in the development of vascular reactivity abnormalities and hypertension. We will test these hypotheses with the following specific aims: Specific Aim 1: To establish an animal model of maternal obesity (overfeeding) in sheep fed a complete balanced diet. Specific Aim 2: To determine if offspring of obese sheep develop alterations in endothelial function/vascular reactivity and/or hypertension. Specific Aim 3: To determine if the offspring of obese sheep exhibit insulin resistance and alterations in adipose tissue hormone and cytokine expression and secretion. PUBLIC HEALTH RELEVANCE: Our proposal will provide an opportunity to study the effect of maternal obesity in an animal model in which much is already known about adipocyte function, and in which the endocrine environment both before and after birth is similar to that of human infants. One of the unique features of our proposal is the study of maternal obesity as a pregestational/gestational continuum, the most common clinical presentation of maternal obesity. The data gathered will serve as the basis for a new application (R01) directed toward identifying the underlying mechanisms for the abnormalities present in the offspring. Future experiments will be conducted at different stages of development to determine the longitudinal nature of any deleterious effects of increased adiposity.