Epigenetic mechanisms in obesity

肥胖的表观遗传机制

• 批准号: 7998396
• 负责人: ROBERT A WATERLAND
• 金额: $ 4.46万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-21 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998396
• 关键词: Adult; Affect; Age; Animal Model; Birth; Body Weight; Candidate Disease Gene; DNA Methylation; Developed Countries; Development; Diet; Environment; Epigenetic Process; Etiology; Female of child bearing age; Figs - dietary; Food Intake Regulation; Fostering; Gene Expression; Gene Expression Regulation; Genes; Genetic Predisposition to Disease; Genetic Variation; Human; Hypothalamic structure; Individual; Lactation; Leptin; Measurement; Measures; Melanocortin 4 Receptor; Methylation; Modeling; Mus; Mutation; Obesity; Pathway interactions; Pattern; Pregnancy; Prevalence; Regulation; Relative (related person); Research; Severities; Site; Specificity; Staging; Stimulus; Testing; Tissues; Variant; Weaning; Weight Gain; bisulfite; design; effective intervention; energy balance; epigenetic variation; fetal; gene function; genome-wide; mouse model; nutrition; offspring; postnatal; prenatal; prevent; public health relevance; trend

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.

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症患病率急剧增加。这种趋势正在影响每个年龄的人，包括儿童年龄的妇女。一个主要问题是，怀孕期间的孕产妇肥胖可能会改变宫内环境，从而使她的后代肥胖永存。可行的黄色Agouti（Avy）小鼠是探索母体肥胖和饮食对后代体重的影响的理想模型。 Avy/A小鼠是自发的，并且会发展成人肥胖。然而，肥胖的严重程度在等源性AVY/A小鼠中是高度变化的。拟议研究的总体假设是，在发育中的下丘脑中，妊娠和/或泌乳期间的母体肥胖会影响基因特异性DNA甲基化模式的建立，从而导致下丘脑基因表达，食物摄入量调节和体重的永久变化。该项目的具体目的是：1）表征在下丘脑基因上DNA甲基化的发展和组织特异性影响食物摄入调节的基因，2）在Avy小鼠模型中，在Avy小鼠模型中，确定孕产妇肥胖对后代体重的影响是否在产前或早期发育过程中出现在甲基化和早期的表达过程中，并确定甲基化的特异性，并确定甲基化的特异性，以甲基化的特异性，以甲基化的态度，以甲基化的态度，以甲基化的态度，以甲基化的态度，均具有甲基化的表达。与肥胖有关。动物模型中的这项研究对于阐明孕产妇肥胖影响后代体重的机制是必要的。这些信息将使我们能够准确衡量这种现象对人肥胖病因的影响并可能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，在发育中的下丘脑中，怀孕期间和/或泌乳期间的肥胖会影响基因特异性DNA甲基化模式的建立，从而导致下丘脑基因表达，食物摄入量调节，体重和体重的永久变化。我们将在有或没有肥胖症遗传易感性的小鼠中研究这一假设。我们的结果将阐明产妇肥胖影响后代体重的机制，从而使我们能够准确评估这种现象对人肥胖病因的影响，并最终设计有效的干预措施。