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: 7289744
• 负责人: Timothy H Moran
• 金额: $ 32.9万
• 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/7289744
• 关键词: Address; Adolescence; Adult; Affect; Animal Model; Behavioral; Body Weight; Cardiovascular Diseases; Characteristics; Clinical; Condition; Consumption; DNA Methylation Regulation; Data; Development; Diet; Discipline of Nursing; Endocrine; Environment; Epigenetic Process; Etiology; Exposure to; Fatty acid glycerol esters; Fetal Growth Retardation; Fetus; Future; Genes; Goals; Health; Homeostasis; Hypertension; Hypothalamic structure; Insulin Resistance; Intervention; Lactation; Lead; Life; Life Style; Long-Term Effects; Mediating; Metabolic; Metabolic Diseases; Methylation; Modeling; Modification; Neonatal; Neural Pathways; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Organism; Phenotype; Predisposition; Pregnancy; Public Health; Rattus; Regulation; Risk; Role; Signal Transduction; Sprague-Dawley Rats; System; Testing; Time; Work; base; critical developmental period; day; energy balance; feeding; metabolic abnormality assessment; nutrition; prevent; pup; research study; response

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）：肥胖是一个全球性的公共卫生问题，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。流行病学数据表明，母亲营养不足可导致胎儿宫内发育迟缓，对后代造成长期后果，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，产妇营养过剩可能产生类似的长期后果。具体而言，现代西方生活方式的特征是母亲食用高脂肪饮食，这已被证明会导致后代的代谢紊乱，如肥胖和胰岛素抵抗。对引起产妇营养过剩后果的机制还不十分了解。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体食用高脂肪饮食并导致肥胖的短期和长期影响。特定实验解决了RFA的许多方面，因为它们将：1）表征适合研究母体高脂肪饮食消费和肥胖的代谢后果的动物模型，2）定义对能量平衡所涉及的神经通路上的代谢扰动敏感的关键时期，以及3）研究表观遗传变化作为介导机制的作用。具体目标是：1）确定在肥胖倾向的Sprague道利大鼠中由母体高脂肪饮食消耗引起的行为和内分泌改变的发育时程，2）为了检验母体高脂肪饮食消耗产生参与能量平衡的下丘脑神经肽信号传导系统的改变的假设，所述改变使发育中的幼仔偏向肥胖和代谢紊乱，以及3）确定高脂肪饮食是否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甲基化的调控，并且在暴露于母体高脂肪饮食和肥胖时发生差异甲基化。这些实验的结果将增强我们对肥胖和代谢性疾病的病因学的理解，最终允许为此类疾病开发合理的临床干预措施。