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

描述(申请人提供)：肥胖是一个世界性的公共卫生问题，最近的研究表明，母亲营养状况的变化可能会增加肥胖的风险。流行病学数据表明，母亲营养不良会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，产妇过度营养可能会产生类似的长期后果。具体地说，母亲食用高脂肪饮食是现代西方生活方式的特征，已被证明会导致后代出现肥胖和胰岛素抵抗等新陈代谢障碍。调节产妇过度营养后果的机制还不是很清楚。这项建议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摄入高脂肪饮食和由此导致的肥胖的短期和长期影响。这些具体的实验涉及RFA的许多方面，因为它们将：1)表征适合于研究母亲高脂饮食和肥胖的代谢后果的动物模型，2)确定代谢扰动对涉及能量平衡的神经通路的关键敏感时期，以及3)研究表观遗传变化作为中介机制的作用。其具体目的是：1)确定母亲摄入高脂饮食导致肥胖易感SD大鼠行为和内分泌变化的发育时间进程；2)测试母亲摄入高脂饮食会导致下丘脑神经肽信号系统发生变化的假说，该系统参与能量平衡，使发育中的幼鼠倾向于肥胖和代谢紊乱；3)确定高脂饮食是否通过表观遗传修饰导致后代肥胖和代谢障碍。我们假设，对能量平衡至关重要的基因受到DNA甲基化的调节，并因暴露于母亲的高脂肪饮食和肥胖而出现差异甲基化。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理解，最终允许针对这些情况开发合理的临床干预措施。

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.