Nutrient and Insulin Metabolic Actions in IUGR Fetal Liver

项目摘要 这项建议的目的是确定胎儿缺氧对胎儿发育的分子和代谢影响， 胎肝胰岛素抵抗和胎肝葡萄糖生成率（GPR）激活。这很重要 因为妊娠并发胎盘缺血性疾病，特别是胎盘功能不全 诱导性宫内生长受限（PI-IUGR）使胎儿面临缺氧。我们已经证明胎儿肝脏 在PI-IUGR期间，肝GPR增加，其抵抗胰岛素的抑制。而肝胰岛素 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）的标志，PI-IUGR后代更容易患上这种糖尿病。PI-IUGR胎儿还 葡萄糖氧化能力有限，肝耗氧量降低，表明 线粒体底物氧化，这可能使碳重定向用于GPR。我们的目标是了解 胎儿缺氧时肝脏葡萄糖生成的早期激活机制。整体 该建议的假设是胎儿缺氧是肝胰岛素抵抗的主要驱动力，增加肝胰岛素抵抗， 葡萄糖的产生，以及胎儿肝脏线粒体氧化的减少。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，增加肝脏葡萄糖的产生， 降低肝线粒体氧化。在目标2中，我们将确定慢性胎儿缺氧是否会 肝脏胰岛素抵抗通过增加核FOXO 1和降低AMPK活性导致增加 PCK 1和PDK 4在胎肝中的表达。在目标3中，我们将确定 分离的肝细胞中的葡萄糖产生和线粒体氧化。我们的研究结果将使我们 确定胎儿肝脏缺氧对肝GPR激活和发育的具体作用 肝脏胰岛素抵抗我们还将确定参与GPR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缺氧和相对低血糖 作为胎儿肝GPR的主要原因。胎儿肝脏是PI-IUGR发病最严重的器官之一 也是唯一表现出胰岛素抵抗的胎儿器官，这是以后生活中T2 DM的标志。定义胎儿缺氧 作为早期驱动因素，缺氧诱导的病理生理适应可能是 了解胎儿缺氧如何编程胎儿肝脏产生葡萄糖， 在以后的生活中发展为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.