Maternal Obesity: A Sheep Model

母亲肥胖：绵羊模型

• 批准号: 7617637
• 负责人: JORGE Pablo FIGUEROA
• 金额: $ 22.2万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617637
• 关键词: Address; Adipocytes; Adipose tissue; Adolescent; Adult; Animal Model; Attention; Basic Science; Birth; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Child; Clinical; Coronary heart disease; Data; Development; Diet; Disease; Dyslipidemias; Elements; Endocrine; Environment; Epidemiologic Studies; Equilibrium; Event; Exhibits; Female; Fetus; Future; Gestational Age; Gestational Diabetes; Glucose Intolerance; Goals; Health; Hormonal; Hormones; Human; Hypertension; Individual; Infant; Insulin Resistance; Interleukin-6; Lead; Leptin; Life; Literature; Long-Term Effects; Low Birth Weight Infant; Metabolic syndrome; Metabolism; Modeling; Mothers; Nature; Newborn Infant; Obesity; Physiology; Play; Pregnancy Outcome; Prevalence; Production; Regulation; Risk; Role; Sheep; Staging; Stimulus; Structure; Syndrome; TNF gene; Testing; adiponectin; adrenal hypertension; base; cardiovascular risk factor; cytokine; feeding; fetal; fetal programming; hypertensive heart disease; in utero; obesity in children; offspring; pregnant; prenatal; programs; public health relevance; research study; resistin; response

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.

描述(由申请人提供：对于胎龄较小的新生儿(SGA)和较大的(LGA)新生儿，出生体重与日后发生冠心病的风险之间存在关联。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。母体肥胖和妊娠期糖尿病(GDM)是LGA新生儿的主要决定因素。在这些情况中，母亲肥胖作为一种潜在的产前侮辱导致胎儿规划的问题几乎没有受到关注。这项建议的目标是开发一种母体肥胖的动物模型，以便研究胎儿对母体肥胖症和/或出生时LGA的适应增加发生心血管疾病的风险的机制。我们的全球假设是，肥胖母亲的后代在脂肪组织中有永久性的变化，这使他们容易在内皮功能/血管反应性和高血压以及成年生活中出现异常。因此，我们认为：1)肥胖孕妇的母体环境引起胎儿适应，对子代脂肪组织的调节和功能产生长期影响；2)肥胖母亲子代脂肪组织中激素(脂联素、瘦素、抵抗素)和细胞因子(肿瘤坏死因子、IL-6和C反应蛋白)的产生和分泌发生改变；3)脂肪组织产生和/或激素和细胞因子的分泌改变在血管反应性异常和高血压的发生中起核心作用。我们将通过以下具体目标来检验这些假说：具体目标1：建立完全均衡饮食的绵羊母体肥胖(过度喂养)的动物模型。具体目标2：确定肥胖绵羊的后代是否会出现内皮功能/血管反应性和/或高血压的变化。具体目的3：确定肥胖绵羊的后代是否存在胰岛素抵抗以及脂肪组织激素和细胞因子的表达和分泌的变化。公共卫生相关性：我们的建议将提供一个机会，在一个动物模型中研究母体肥胖的影响，在这个动物模型中，脂肪细胞的功能已经很清楚，而且出生前后的内分泌环境与人类婴儿的内分泌环境相似。我们建议的独特特征之一是将母亲肥胖作为孕前/妊娠连续统一体进行研究，这是母亲肥胖最常见的临床表现。收集的数据将作为新应用程序(R01)的基础，该应用程序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。