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

非人灵长类动物 (NHP) 胎儿肝脏编程机制

基本信息

批准号：
7296625
负责人：
JACOB E FRIEDMAN
金额：
$ 36.48万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-09 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7296625
关键词：
1,2-diacylglycerol Address Adolescent Adult Age Animal Model Animals Biochemical Biological Markers Body Weight CCL2 gene Cardiovascular Diseases Ceramides Child Childhood Chronic Collaborations Consumption Coupled DEXA Data Development Diabetes Mellitus Diabetic mother Diet Diglycerides Distress Enzyme-Linked Immunosorbent Assay Epidemic Euglycemic Clamping Exposure to Fatty Liver Fatty acid glycerol esters Fetal Development Fetal Liver Fetus Future Genes Gluconeogenesis Glucose Glucose Clamp Goals Health Sciences Heat shock proteins Hepatic Hepatic Tissue Hepatocyte High Density Lipoprotein Cholesterol Homeostasis Human Hyperinsulinism Immunohistochemistry In Situ Hybridization Individual Inflammation Inflammatory Infusion procedures Insulin Resistance Interleukin-6 LTA gene Lead Leptin Life Lipids Liver Long-Term Effects Malonyl Coenzyme A Measures Mediating Messenger RNA Metabolic Metabolic Diseases Modeling Molecular Monitor Morbidity - disease rate Mothers Muscle Numbers Nutrient Obesity Oregon Outcome Overnutrition Oxidative Stress Pattern Peripheral Phenotype Phosphoenolpyruvate Carboxylase Phosphotransferases Polymerase Chain Reaction Predisposition Pregnancy Prevalence Primates Public Health Research Research Personnel Risk Screening procedure Signal Transduction Stress Testing Therapeutic Time Tissues Transcriptional Activation Triglycerides Tumor Necrosis Factor-Beta Uncertainty Universities Up-Regulation Weaning Weight Gain Western Blotting adiponectin base chemokine cysteine rich protein cytokine day diabetic fatty acid oxidation feeding fetal fetal programming glucose production in utero insight insulin signaling liver biopsy monocyte non-diabetic nonalcoholic steatohepatitis nonhuman primate novel oxidation prevent programs receptor stable isotope

项目摘要

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.

描述（由申请人提供）：当前儿童肥胖的流行，加上孕产妇肥胖患病率的不断增加，令人担忧，即孕产妇肥胖（与糖尿病无关）可能会导致胎儿肥胖及其并发症。来自人类和动物研究的证据表明，在胎儿期接触高营养供应的个体有很高的儿童和成人肥胖风险。很明显，患有糖尿病的母亲所生的孩子肥胖率更高，并且存在胰岛素抵抗。有人提出儿童肥胖与没有糖尿病或怀孕期间体重增加的母亲肥胖之间存在关联，但尚不清楚。我们与俄勒冈健康与科学大学合作，开发了高脂肪/热量饮食引起的母亲肥胖/糖尿病的非人类灵长类动物 (NHP) 模型，以确定对后代体重稳态的直接和长期影响。我们小组在暴露于慢性（2-3岁）母体高脂肪饮食的 NHP 胎儿肝脏中获得的试点数据显示了一种新的转录调节模式（HNF4a、PEPCK、热休克蛋白基因增加），该模式是两种潜在重要异常的基础：脂肪变性和过早糖异生。此外，微阵列和组织学证据表明，高脂肪饮食母亲的胎儿肝脏会形成慢性炎症模式，与氧化应激和非酒精性脂肪性肝炎 (NASH) 相关。该计划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，1. 确定怀孕期间的高脂肪喂养如何引发胎儿生命期间肝脏燃料传感网络关键方面的失调。 2. 确定这些变化对产后生活中胰岛素抵抗和肥胖的影响。 3. 确定肥胖/糖尿病母亲仅在怀孕期间转向低脂肪/热量饮食是否可以预防胎儿代谢异常的发生。燃料介导的编程可能是由孕产妇营养过剩和肥胖驱动的假设对公共健康造成了巨大的影响。这些研究将为儿童和成人代谢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来阻止青少年肥胖及其破坏性的疾病。 -发病率。