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

描述（由申请人提供）：目前儿童肥胖的流行，加上孕产妇肥胖的日益流行，引起了令人不安的担忧，即与糖尿病无关的孕产妇肥胖可能会导致胎儿肥胖及其合并症。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在儿童和成人中成为肥胖的风险很高。很明显，患有糖尿病的母亲所生的孩子会增加肥胖，并产生胰岛素抵抗。儿童期肥胖与未患糖尿病或孕期体重增加的产妇肥胖之间存在关联，但尚不清楚。我们与俄勒冈健康与科学大学合作，开发了一种非人类灵长类动物（NHP）高脂肪/卡路里饮食诱导的母亲肥胖/糖尿病模型，以确定对后代体重稳态的即时和长期影响。本研究小组在慢性（2-3年）母体高脂肪饮食的新生儿肝脏中获得的初步数据显示，一种新的转录调节模式（HNF4a、PEPCK、热休克蛋白基因增加）是两种潜在重要异常的基础：肝脂肪变性和过早糖异生。此外，微阵列和组织学证据表明，高脂肪饮食的母亲的胎儿肝脏发展成慢性炎症模式，与氧化应激和非酒精性脂肪性肝炎（NASH）相关。这个项目的主要目标是与俄勒冈国家灵长类动物研究中心的研究人员合作。确定孕期高脂肪喂养如何引发胎儿期肝脏燃料感知网络关键方面的失调。2. 确定这些变化对产后胰岛素抵抗和肥胖的影响。3. 确定在怀孕期间将肥胖/糖尿病母亲转换为低脂肪/卡路里饮食是否可以预防胎儿代谢异常的发展。假设燃料介导的编程可能是由母亲营养过剩和肥胖驱动的，这种假设对公共卫生的影响是巨大的。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，并将为未来的研究奠定重要的基础，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的合并症。

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.