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）：肥胖是一个世界范围的公共卫生问题，最近的研究表明，母亲营养状况的改变可能会增加肥胖的风险。流行病学数据显示，母亲营养不良可导致宫内生长迟缓，对后代产生长期影响，包括高血压、心血管疾病、2型糖尿病和肥胖。现在有证据表明，母亲营养过剩可能会产生类似的长期后果。具体来说，母亲食用高脂肪饮食（现代西方生活方式的特征）已被证明会导致后代肥胖和胰岛素抵抗等代谢紊乱。调节孕产妇营养过剩后果的机制尚不清楚。该提案的总体目标是在多基因饮食诱导的肥胖大鼠模型中表征母亲食用高脂肪饮食并导致肥胖的短期和长期影响。具体实验涉及 RFA 的许多方面，因为它们将：1）描述适合研究母亲高脂肪饮食消耗和肥胖的代谢后果的动物模型，2）定义参与能量平衡的神经通路代谢扰动的关键时期，3）研究表观遗传变化作为调节机制的作用。具体目标是：1) 确定易肥胖斯普拉格道利大鼠因母亲高脂肪饮食摄入而导致行为和内分泌改变的发育时间过程，2) 检验母亲摄入高脂肪饮食会导致参与能量平衡的下丘脑神经肽信号系统发生改变，从而使发育中的幼鼠偏向肥胖和代谢紊乱的假设，以及 3) 确定高脂肪饮食是否会导致 通过表观遗传修饰导致后代肥胖和代谢紊乱。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，并且因暴露于母亲高脂肪饮食和肥胖而发生差异甲基化。这些实验的结果将增强我们对肥胖和代谢疾病病因学的理解，最终为此类疾病制定合理的临床干预措施。