Influences of the prenatal environment on metabolic programming

肥胖是一个全球性的主要公共卫生问题，最近的研究表明， 次优的早期环境可能增加变得肥胖的风险。流行病学数据显示， 不利的子宫内环境对后代具有长期的后果，包括高血压， 心血管疾病、2型糖尿病、肥胖症和神经精神疾病。特别是产前压力 和/或消耗高脂肪饮食的现代人类生活方式的特征，已经被证明， 导致后代代谢紊乱如肥胖和胰岛素抵抗。然而，机制 所涉及的问题并没有得到很好的理解。本提案的总体目标是描述短期和长期 产前环境的变化-压力和营养-对行为和生理的影响 并探讨可能的神经肽和表观遗传机制参与 使用大鼠动物模型。具体目标是：1）确定行为的发展时间进程， 以及产前压力导致的内分泌改变我们还将检验产前压力 将加重饮食引起的肥胖，哺乳期、青春期和成年期的时间点将 检查以表征表型并直接检查可能的机制; 2）测试 假设产前压力，高脂肪饮食，或两者都导致神经肽系统调节的改变， 能量稳态与其他啮齿动物肥胖模型一致;和3）为了检验假设 产前压力和营养通过表观遗传修饰， 差异DNA甲基化的基因是至关重要的能量稳态。这些实验将 提高我们对肥胖和代谢疾病病因学的理解， 为此类疾病制定合理的临床干预措施。

Obesity Is a major public health problem worldwide and recent work has suggested that exposure to a suboptimal eariy environment may increase the risk of becoming obese. Epidemiological data show that an unfavorable intrauterine environment has long-term consequences in offspring including hypertension, cardiovascular disease, type 2 diabetes, obesity and neuropsychiatric disease. Specifically, prenatal stress and/or consumption of a high fat dieL characteristics of modern day human lifestyle, have been shown to lead to metabolic disorders such as obesity and Insulin resistance in offspring. However, the mechanisms involved are not well understood. The overall goal of this proposal is to characterize the short- and long-tenn effects of changes in the prenatal environment - stress and nutrition - on the behavioral and physiological development of offspring and to explore the possible neuropeptide and epigenetic mechanisms involved using a rat animal model. Specific aims are: 1) To detemiine the developmental time course of behavioral and endocrine alterations resulting from prenatal stress. We will also test the hypothesis that prenatal stress will accentuate diet-induced obesity, Timepoints during lactation, adolescence, and adulthood will be examined to characterize the phenotype and to direct examination of possible mechanisms; 2) To test the hypothesis that prenatal stress, high fat diet, or both result in alterations in neuropeptide systems regulating energy homeostasis that are consistent with other rodent models of obesity; and 3) To test the hypothesis that prenatal stress and nutrition results in obesity in offspring through epigenetic modifications via differential DNA methylation of genes that are critical to energy homeostasis. 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.