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

描述（由申请人提供）：目前儿童肥胖症流行，加上母亲肥胖症患病率的增加，引起了令人不安的担忧，即母亲肥胖症（与糖尿病无关）可能导致胎儿肥胖症及其合并症。来自人类和动物研究的证据表明，在胎儿期暴露于高营养供应的个体具有成为肥胖儿童和成人的高风险。很明显，患有糖尿病的母亲所生的孩子肥胖增加，并且具有胰岛素抵抗。儿童肥胖和母亲肥胖之间的联系没有糖尿病或体重增加在怀孕期间已经提出，但不太清楚。与俄勒冈州健康与科学大学合作，我们开发了一种非人灵长类动物（NHP）高脂肪/热量饮食诱导的母体肥胖/糖尿病模型，以确定对后代体重稳态的直接和长期影响。我们的小组在暴露于慢性（2-3年）母体高脂饮食的NHP胎肝中获得的初步数据显示了一种新的转录调控模式（增加的HNF 4a，PEPCK，热休克蛋白基因），这是两种潜在的重要异常的基础：肝脂肪变性和过早的新生儿。此外，微阵列和组织学证据表明，来自高脂肪饮食母亲的胎儿肝脏发展出一种慢性炎症模式，与氧化应激和非酒精性脂肪性肝炎（NASH）相关。该项目的主要目标是与俄勒冈州国家灵长类动物研究中心的研究人员合作，确定怀孕期间高脂肪喂养如何触发胎儿生命期间肝脏燃料感知网络关键方面的失调。2.确定这些变化对出生后胰岛素抵抗和肥胖的影响。3.确定在怀孕期间将肥胖/糖尿病母亲转变为低脂/低热量饮食是否可以预防胎儿代谢异常的发展。假设燃料介导的规划可能是由产妇营养过剩和肥胖症驱动的，这对公共卫生的影响是巨大的。这些研究将为其他动物模型中不可能的儿童和成人代谢疾病易感性的基本分子机制提供重要见解，并将为未来旨在开发安全有效的治疗方法以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.