MECHANISMS FOR FETAL HEPATIC PROGRAMMING IN THE NON-HUMAN PRIMATE (NHP)

描述(申请人提供)：目前儿童肥胖症的流行，加上产妇肥胖率的上升，引发了令人担忧的担忧，即独立于糖尿病之外的产妇肥胖症可能有助于胎儿规划肥胖症及其共病。来自人类和动物研究的证据表明，在胎儿时期暴露于高营养供应的个人有很高的风险成为肥胖的儿童和成年人。很明显，糖尿病母亲所生的孩子会增加肥胖，并对胰岛素产生抵抗。儿童肥胖和没有糖尿病或怀孕期间体重增加的母亲肥胖之间的联系已经被提出，但不太清楚。我们与俄勒冈健康与科学大学合作，开发了一个非人类灵长类动物(NHP)模型，研究高脂肪/高热量饮食诱导的母体肥胖/糖尿病，以确定对子代体重动态平衡的即时和长期影响。我们小组在长期(2-3年)母亲高脂饮食暴露的NHP胎肝中获得的初步数据显示了一种新的转录调控模式(HNF4a、PEPCK、热休克蛋白基因增加)，这是两种潜在的重要异常的基础：肝脏脂肪变性和过早的糖异生。此外，基因芯片和组织学证据表明，喂养高脂肪饮食的母亲的胎儿肝脏会发展成一种慢性炎症模式，与氧化应激和非酒精性脂肪性肝炎(NASH)相关。该项目的主要目标(S)是与俄勒冈州国家灵长类动物研究中心的研究人员合作，以1.确定怀孕期间高脂肪喂养如何触发胎儿时期肝脏燃料传感网络关键方面的失调。2.确定这些变化对出生后生活中胰岛素抵抗和肥胖的影响。3.确定肥胖/糖尿病母亲在怀孕期间单独改变为低脂肪/低卡路里饮食是否可以防止胎儿代谢异常的发展。燃料介导的编程可能是由母亲营养过剩和肥胖推动的假设对公共健康的影响是巨大的。这些研究将为儿童和成人代谢性疾病易感性的基本分子机制提供重要的见解，这在其他动物模型中是不可能的，并将为未来旨在开发安全有效的治疗方法来阻止青少年肥胖及其毁灭性共病的研究奠定重要基础。

DESCRIPTION (provided by applicant): The current childhood obesity epidemic, coupled with the increasing prevalence of maternal obesity raise the distressing concern that maternal obesity, independent of diabetes, may be contributing to fetal programming of obesity and its co-morbidities. Evidence from human and animal studies suggests that individuals exposed to a high nutrient supply during fetal life have a high risk of becoming obese children and adults. It is clear that children born to diabetic mothers have increased adiposity and are insulin resistant. Associations between childhood obesity and maternal obesity without diabetes or weight gain during pregnancy have been suggested, but are less clear. In collaboration with the Oregon Health and Sciences University, we have developed a nonhuman primate (NHP) model of high fat/calorie diet-induced maternal obesity/diabetes in order to determine the immediate and long-term effects on body weight homeostasis in the offspring. Pilot data obtained by our group in the fetal liver of NHP exposed to chronic (2-3 yr) maternal high fat diet show a novel transcriptional regulatory pattern (increased HNF4a, PEPCK, Heat Shock Protein Genes) that underlies two potentially important abnormalities: hepatic steatosis and premature gluconeogenesis. In addition, microarray and histological evidence suggests fetal livers from mothers fed a high fat diet develop a pattern of chronic inflammation, associated with oxidative stress and non-alcoholic steatohepatitis (NASH). The major goal(s) of this program is to collaborate with investigators at the Oregon National Primate Research Center to 1. Identify how high fat feeding during pregnancy triggers dysregulation of key aspects in hepatic fuel sensing network during fetal life. 2. Determine the impact of these changes on insulin resistance and obesity during post-natal life. 3. Determine if switching obese/diabetic mothers to a low fat/calorie diet during pregnancy alone can prevent the development of metabolic abnormalities in the fetus. The public health consequences of the hypothesis that fuel-mediated programming may be driven by maternal overnutrition and obesity are enormous. These studies will provide critical insights into the fundamental molecular mechanisms underlying susceptibility to pediatric and adult metabolic disease not possible in other animal models, and will lay important groundwork for future studies aimed at developing safe and effective therapeutic approaches to halting juvenile obesity and its devastating co-morbidities.