Metabolic and Epigenetic Effects of Maternal High Fat Diet in Obesity Prone Rats

母亲高脂肪饮食对肥胖倾向大鼠的代谢和表观遗传影响

• 批准号: 7233790
• 负责人: Timothy H Moran
• 金额: $ 33.78万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2010-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7233790
• 关键词: DNA methylation; behavior test; bioenergetics; biological signal transduction; dietary lipid; disease /disorder model; disease /disorder proneness /risk; endocrine gland /system; enzyme linked immunosorbent assay; epigenetics; genetic susceptibility; glucose tolerance test; growth /development; hypothalamus; in situ hybridization; laboratory rat; maternal behavior; metabolic syndrome; mother /embryo /fetus nutrition; neuropeptides; nutrient intake activity; nutrition related tag; obesity; pathogenic diet; tissue /cell preparation

DESCRIPTION (provided by applicant): Obesity is a worldwide public health problem and recent work has suggested that alterations in maternal nutritional status may increase the risk of becoming obese. Epidemiological data have shown that maternal under-nutrition can lead to intrauterine growth retardation with long-term consequences to offspring including hypertension, cardiovascular disease, type 2 diabetes and obesity. Evidence is now emerging that maternal over-nutrition may have similar long-term consequences. Specifically, maternal consumption of a high fat diet, characteristic of the modern day Western lifestyle, has been shown to lead to metabolic disorders such as obesity and insulin resistance in offspring. The mechanisms mediating the consequences of maternal over-nutrition are not well understood. The overall goal of this proposal is to characterize the short- and long-term effects of maternal consumption of a high fat diet and resulting obesity in a polygenic diet induced rat model of obesity. The specific experiments address numerous aspects of the RFA in that they will: 1) characterize an animal model appropriate for the study of metabolic consequences of maternal high fat diet consumption and obesity, 2) define critical periods of susceptibility to metabolic perturbations on neural pathways involved in energy balance and 3) investigate the role of epigenetic changes as mediating mechanisms. The specific aims are: 1) To determine the developmental time course of behavioral and endocrine alterations resulting from maternal high fat diet consumption in obesity prone Sprague Dawley rats, 2) To test the hypothesis that maternal consumption of high fat diet produces alterations in hypothalamic neuropeptide signaling systems involved in energy balance that bias the developing pups toward obesity and metabolic disturbances, and 3) To determine whether high fat diet results in obesity and metabolic disturbances in offspring through epigenetic modifications. We hypothesize that genes that are critical to energy homeostasis are subject to regulation by DNA methylation and are differentially methylated in response to exposure to maternal high fat diet consumption and obesity. The results of these experiments will enhance our understanding of the etiology of obesity and metabolic disease ultimately allowing the development of rational clinical interventions for such conditions.

描述（由申请人提供）：肥胖是一个全球公共卫生问题，最近的工作表明，孕产妇营养状况的改变可能会增加肥胖的风险。流行病学数据表明，孕产妇不足会导致宫内生长迟缓，对后代的长期后果，包括高血压，心血管疾病，2型糖尿病和肥胖症。现在有证据表明，孕产妇的过度营养可能会带来相似的长期后果。具体而言，现代西方生活方式的特征的高脂饮食的母体消费已被证明会导致后代的代谢疾病，例如肥胖和胰岛素抵抗。介导的孕产妇过度营养后果的机制尚不清楚。该提案的总体目标是表征产妇消耗高脂饮食的短期和长期影响，并在多基因饮食诱发的大鼠肥胖模型中产生肥胖。特定的实验涉及RFA的许多方面，因为它们将：1）表征适合于研究母体高脂饮食消耗和肥胖的代谢后果的动物模型，2）定义对能量涉及的神经途径涉及能量平衡的神经途径的易感性的关键时期；具体目的是：1）确定肥胖症中孕妇高脂饮食量导致的行为和内分泌改变导致的发育时间过程，容易发生肥胖的sprague dawley大鼠，2）测试假说，高脂饮食的孕产妇消耗产生的假设会导致在能量中涉及的能量涉及的高刺激性的饮食效果，并在饮食中取得了影响，并确定puias的高度效果，并在饮食中取得了良好的效果。通过表观遗传修饰，后代的肥胖和代谢障碍。我们假设对能量稳态至关重要的基因受到DNA甲基化的调节，并且由于暴露于母体高脂饮食的消耗和肥胖而被差异化甲基化。这些实验的结果将增强我们对肥胖症和代谢疾病的病因的理解，最终允许在这种情况下发展理性的临床干预措施。