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: 7449821
• 负责人: Timothy H Moran
• 金额: $ 1.03万
• 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/7449821
• 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

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.

肥胖是一个世界性的公共健康问题，最近的研究表明，母体肥胖的改变 营养状况可能会增加肥胖的风险。流行病学数据表明，产妇 营养不良会导致宫内发育迟缓，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，母亲 过度营养可能会产生类似的长期后果。具体地说，孕妇摄入的高脂肪 饮食，现代西方生活方式的特征，已被证明会导致新陈代谢紊乱，如 与后代的肥胖和胰岛素抵抗有关。母婴传播后果的调节机制 营养过剩还没有得到很好的理解。这项提案的总体目标是描述短期和 母亲食用高脂肪饮食并导致多基因饮食导致肥胖的长期影响 肥胖大鼠模型。具体的实验涉及RFA的许多方面，因为它们将：1) 描述一种适合研究母体高脂肪饮食代谢后果的动物模型 消费与肥胖，2)定义神经易受代谢紊乱影响的关键时期 参与能量平衡的途径和3)研究表观遗传变化作为中介的作用 机制。其具体目标是：1)确定行为和行为发育的时间进程 肥胖易感Spraogue Dawley母亲高脂饮食摄入引起的内分泌改变 大鼠，2)检验母亲食用高脂肪饮食会导致 参与能量平衡的下丘脑神经肽信号系统对发育中的幼鼠产生偏向 肥胖和代谢紊乱，以及3)确定高脂肪饮食是否导致肥胖和 通过表观遗传修饰在后代中的代谢障碍。我们假设基因是 对能量平衡至关重要的基因受到DNA甲基化的调节，并存在差异甲基化 以应对母亲暴露于高脂肪饮食和肥胖的情况。这些实验的结果 将加强我们对肥胖和代谢性疾病的病因的了解，最终使 针对这种情况开发合理的临床干预措施。