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程序如何改变胎儿代谢，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性疾病的易感性。我们最近的数据表明，在胎儿生命中通常不存在的葡萄糖产生和糖异生基因表达在妊娠晚期IUGR胎羊中显著上调。我们的数据还表明，胰岛素不能抑制IUGR胎儿的葡萄糖产生，但却显著提高了全身葡萄糖利用和氧化率，这表明IUGR胎儿产生了肝脏特异性胰岛素抵抗，但增加了外周胰岛素作用。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，来测试IUGR胎儿在牺牲躯体生长的情况下，在胰岛素敏感性和代谢方面发展出组织特异性适应的假设。具体而言，我将掌握胎儿肝脏和后肢导管制备的外科技术，并开发新的示踪方法，用于测量整个胎儿以及包括肝脏和后肢在内的特定组织的葡萄糖和乳酸代谢，代表骨骼肌作为其代谢活性成分。我将开发核磁共振代谢组学技术来测量组织代谢物，包括糖酵解、糖异生和TCA循环的中间体、辅助因子和底物。在分子水平上，我将获得核功能分析、基因调控和表观遗传学方面的专业知识，以确定肝脏和骨骼肌差异胰岛素敏感性的机制。该提案中概述的核心实验室，教师指导和培训计划将使我能够在执行这些方法方面进行高级培训，这些方法是我职业发展道路上的重要步骤，旨在了解整个动物，器官/组织和分子水平上胎儿代谢编程的机制。这些研究将为IUGR胎儿的葡萄糖和乳酸代谢、胰岛素作用以及胎儿肝脏和骨骼肌之间的代谢协调提供新的信息。这些研究还将对信号蛋白的早期发展和IUGR与肝脏中葡萄糖产生增加和胰岛素抵抗的途径以及促进骨骼肌中葡萄糖摄取和利用的机制产生重要的概念。

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.