Nutrient and Insulin Metabolic Actions in IUGR Fetal Liver

项目总结 这项建议的目的是确定胎儿缺氧在发育中的分子和代谢影响。 胎肝胰岛素抵抗与活化胎肝葡萄糖生成率(GPR)的关系。这事很重要 因为妊娠合并胎盘缺血性疾病，特别是胎盘功能不全 诱导性宫内生长受限(PI-IUGR)使胎儿暴露在低氧环境中。我们已经证明了胎儿肝脏 PI-IUGR期间肝脏GPR升高，对胰岛素抑制有抵抗作用。而肝脏胰岛素 抵抗和GPR增加可能是PI-IUGR胎儿的重要适应，这些事件也是早期的关键 2型糖尿病(T2 DM)的特征，PI-IUGR后代更容易患上这种疾病。PI-IUGR胎儿也 限制了葡萄糖的氧化能力，降低了肝脏的耗氧量，表明 线粒体底物氧化，这可能为探地雷达重新定向碳。我们的目标是了解 胎儿缺氧时肝脏葡萄糖生成早期激活的机制。整体而言 这一建议的假设是胎儿缺氧是肝脏胰岛素抵抗的主要驱动因素，肝脏升高 葡萄糖的产生，并减少了胎儿肝脏线粒体的氧化。在目标1中，我们将测试 胎儿缺氧对肝脏胰岛素抵抗的发展，肝脏葡萄糖产生的增加，以及 减少肝脏线粒体氧化。在目标2中，我们将确定慢性胎儿缺氧是否会产生 肝脏胰岛素抵抗通过核FOXO1增加和AMPK活性降低导致增加 PCK1和PDK4在胎肝中的表达。在目标3中，我们将确定 分离的肝细胞的葡萄糖产生和线粒体氧化。我们的研究结果将使我们能够 探讨胎肝低氧对肝脏GPR活化和发育的影响 肝脏胰岛素抵抗。我们还将确定GPR中涉及的分子和代谢途径 是由胎儿肝脏中的缺氧调节的。我们的研究还将区分低氧和相对低血糖 作为胎儿肝脏GPR的主要原因。胎儿肝脏是受PI-IUGR影响最严重的器官之一 也是唯一一个表现出胰岛素抵抗的胎儿器官，这是晚年T2 DM的一个标志。定义胎儿缺氧 作为早期驱动因素，低氧诱导的病理生理适应可能是 了解胎儿缺氧是如何使胎儿肝脏产生葡萄糖的，从而建立了 在晚年发展为T2 DM。

PROJECT SUMMARY The goal of this proposal is to define the molecular and metabolic effects of fetal hypoxia on the development of fetal hepatic insulin resistance and activation of fetal hepatic glucose production rate (GPR). This is important because pregnancies complicated by placental ischemic diseases and specifically placental insufficiency induced intrauterine growth restriction (PI-IUGR) expose the fetus to hypoxia. We have shown that the fetal liver during PI-IUGR has increased hepatic GPR, which is resistant to suppression by insulin. While hepatic insulin resistance and increased GPR are likely vital adaptations in the PI-IUGR fetus, these events also are early key hallmarks of type 2 diabetes (T2DM), to which PI-IUGR offspring are more susceptible. The PI-IUGR fetus also has limited glucose oxidation capacity and decreased hepatic oxygen consumption, suggesting decreased mitochondrial substrate oxidation, which may re-direct carbon for GPR. Our goal is to understand the mechanisms for the early activation of hepatic glucose production in response to fetal hypoxia. The overall hypothesis of this proposal is that fetal hypoxia is the major driver of hepatic insulin resistance, increased hepatic glucose production, and decreased hepatic mitochondrial oxidation in the fetus. In Aim 1, we will test the role of fetal hypoxia on the development of hepatic insulin resistance, increased hepatic glucose production, and decreased hepatic mitochondrial oxidation. In Aim 2, we will determine whether chronic fetal hypoxia produces hepatic insulin resistance via increased nuclear FOXO1 and decreased AMPK activity resulting in increased PCK1 and PDK4 expression in the fetal liver. In Aim 3, we will determine the synergistic coordination between glucose production and mitochondrial oxidation in isolated hepatocytes. The results of our studies will allow us to determine the specific role of fetal hypoxia in the fetal liver on the activation of hepatic GPR and development of hepatic insulin resistance. We also will identify the molecular and metabolic pathways involved in GPR that are regulated by hypoxia in the fetal liver. Our studies also will differentiate hypoxia from relative hypoglycemia as a principal cause of fetal hepatic GPR. The fetal liver is one of the most severely affected organs by PI-IUGR and the only fetal organ to demonstrate insulin resistance, a hallmark of later life T2DM. Defining fetal hypoxia as an early driving factor and the pathophysiological adaptations induced by hypoxia may represent the key to understanding how fetal hypoxia programs the fetal liver to produce glucose, establishing a direct risk for developing T2DM in later life.