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计划如何改变胎儿的新陈代谢，以及这些变化如何在出生后持续并增加成人代谢性疾病的易感性。在胎儿生命的关键时期，营养供应的减少或增加会对组织和器官的发育和功能产生重大影响，这可能会对营养感知产生永久性影响，并增加成人生活中对代谢性疾病的易感性。我们最近的数据表明，在妊娠晚期IUGR胎羊中，通常不存在的葡萄糖产生和糖异生基因的表达显著上调。我们的数据还表明，胰岛素不能抑制IUGR胎儿体内葡萄糖的产生，但却显著增加了全身葡萄糖的利用率和氧化率，这表明IUGR胎儿出现肝脏特异性胰岛素抵抗，但外周胰岛素作用增强。这一职业发展奖将使用胎儿生理学和新陈代谢的综合方法，结合新的代谢、分子和表观遗传学技术来检验这一假设，即IUGR胎儿在胰岛素敏感性和代谢方面发展出组织特有的适应，是生存所必需的，但代价是躯体生长。具体地说，我将学习胎儿肝脏和后肢导管准备的外科技能，并开发新的示踪方法来测量整个胎儿以及包括肝脏和后肢在内的特定组织中的葡萄糖和乳酸代谢，将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中胰岛素敏感性差异的机制。这份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开展高级培训，这些方法是我职业道路演变中的关键步骤，旨在了解整个动物、器官/组织和分子水平上的胎儿代谢编程机制。这些研究将提供有关IUGR胎儿体内葡萄糖和乳酸代谢及胰岛素作用的新信息，以及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IUGR与肝脏葡萄糖产量增加和胰岛素抵抗相关的信号蛋白和通路的早期发展以及促进骨骼肌葡萄糖摄取和利用的机制的重要概念。

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.