TISSUE SPECIFIC REGULATION OF GLUCOSE METABOLISM AND INSULIN ACTION IN IUGR FETUS

描述（由申请人提供）：我的长期目标是了解营养供应的改变如何影响胎儿代谢，以及这些变化如何在出生后持续存在，并增加对成人代谢疾病的易感性。在胎儿生命的关键时期，营养供应的减少或增加可能对组织和器官的发育和功能产生重大影响，这可能对营养感知产生永久性影响，并增加成年后对代谢疾病的易感性。我们最近的数据表明，葡萄糖的生产和胚胎发育基因的表达，这是正常情况下，在胎儿生命，是显着上调妊娠后期IUGR胎羊。我们的数据还表明，胰岛素不能抑制IUGR胎儿的葡萄糖产生，但强烈增加全身葡萄糖利用率和氧化，这表明IUGR胎儿发展肝脏特异性胰岛素抵抗，但增加外周胰岛素作用。该职业发展奖将使用胎儿生理学和代谢的综合方法，结合新的代谢组学，分子和表观遗传学技术，以测试IUGR胎儿以牺牲体细胞生长为代价，在胰岛素敏感性和生存所需的代谢方面发展组织特异性适应的假设。具体来说，我将获得胎儿肝脏和后肢导管准备的手术技能，并开发新的示踪剂方法，用于测量整个胎儿和特定组织（包括肝脏和后肢）的葡萄糖和乳酸代谢，代表骨骼肌作为其代谢活性成分。我将开发NMR代谢组学技术来测量组织代谢物，包括糖酵解，代谢物生成和TCA循环的中间体，辅因子和底物。在分子水平上，我将获得核功能，基因调控和表观遗传学检测方面的专业知识，以确定肝脏和骨骼肌胰岛素敏感性差异的机制。核心实验室，教师指导和培训计划概述了本提案将允许我在执行这些方法方面进行高级培训，这些方法是我职业生涯发展的重要步骤，旨在了解整个动物水平上的胎儿代谢编程机制，器官/组织和分子水平。这些研究将提供新的信息，葡萄糖和乳酸代谢和胰岛素的行动在IUGR胎儿和胎儿肝脏和骨骼肌之间的代谢协调。这些研究还将产生关于信号蛋白和通路的早期发展的重要概念，这些信号蛋白和通路将IUGR与肝脏中葡萄糖产生增加和胰岛素抵抗以及促进骨骼肌中葡萄糖摄取和利用的机制联系起来。 公共卫生相关性：这些研究对于了解IUGR对胎儿代谢的影响至关重要，并且对于开发新的组织特异性策略至关重要，这些策略旨在逆转和预防不良代谢适应的发展，然后再导致IUGR成年人的后期代谢疾病。

DESCRIPTION (provided by applicant): My long-term goal is to understand how altered nutrient supply programs fetal metabolism and how these changes may persist after birth and increase susceptibility to adult metabolic disease. Decreased or increased nutrient supply during critical periods in fetal life can have a major impact on the development and function of tissues and organs which may have a permanent effect on nutrient sensing and increase susceptibility to metabolic disease in adult life. Our recent data demonstrate that glucose production and gluconeogenic gene expression, which are normally absent during fetal life, are strikingly up-regulated in the late gestation IUGR fetal sheep. Our data also indicate that insulin fails to suppress glucose production in the IUGR fetus, yet robustly increases whole body rates of glucose utilization and oxidation, suggesting that the IUGR fetus develops liver-specific insulin resistance but increased peripheral insulin action. This career development award will use integrative approaches in fetal physiology and metabolism combined with novel metabolomic, molecular, and epigenetic techniques to test the hypothesis that the IUGR fetus develops tissue specific adaptations in insulin sensitivity and metabolism necessary for survival at the expense of somatic growth. Specifically, I will acquire surgical skills for fetal hepatic and hindlimb catheter preparations and develop new tracer methodologies for measurement of glucose and lactate metabolism in the whole fetus and across specific tissues including the liver and hindlimb, representing skeletal muscle as its metabolically active component. I will develop NMR metabolomics techniques to measure tissue metabolites, including intermediates, cofactors, and substrates for glycolysis, gluconeogenesis, and the TCA cycle. At the molecular level, I will gain expertise in assays of nuclear function, gene regulation, and epigenetics to determine mechanisms for differential insulin sensitivity in liver and skeletal muscle. The core laboratories, faculty mentoring, and training plan outlined in this proposal will allow me to develop advanced training in the execution of these methods that are essential steps in the evolution of my career path aimed at understanding the mechanisms for fetal metabolic programming at the level of the whole animal, organ/tissue, and molecular level. These studies will provide novel information regarding glucose and lactate metabolism and insulin action in the IUGR fetus and the coordination of metabolism between the fetal liver and skeletal muscle. These studies will also generate important concepts about the early development of signaling proteins and pathways linking IUGR to increased glucose production and insulin resistance in the liver and mechanisms that promote glucose uptake and utilization in skeletal muscle. PUBLIC HEALTH RELEVANCE: These studies are essential in understanding the effects of IUGR on fetal metabolism and fundamental to developing novel tissue-specific strategies aimed at reversing and preventing the development of adverse metabolic adaptations before they contribute to later life metabolic diseases in adults who were IUGR.