Glucose metabolism in the fetal liver during hypoxia

缺氧时胎儿肝脏的葡萄糖代谢

• 批准号: 9756803
• 负责人: Amanda K Jones
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2019-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756803
• 关键词: Address; Age; Amino Acids; Award; Biological Assay; Blood flow; Carbon; Cell Respiration; Citric Acid Cycle; Data; Development; Diabetes Mellitus; Disease; Elderly; Energy Supply; Ensure; Event; Exposure to; FOXO1A gene; Fetal Growth Retardation; Fetal Liver; Fetal Tissues; Fetus; Foundations; Future; Genes; Genetic Transcription; Glucose; Goals; Hepatic; Hepatocyte; Hypoxia; In Vitro; Individual; Insulin; Kinetics; Knowledge; Late Effects; Learning; Life; Liver; Liver Mitochondria; Measures; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Molecular Target; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Outcome; Oxides; Oxygen Consumption; Pathogenesis; Pathway interactions; Phosphorylation; Physiology; Placental Insufficiency; Pregnancy; Production; Publishing; Research; Research Personnel; Research Technics; Resistance; Risk; Role; Sheep; Signal Pathway; Signal Transduction; Small Interfering RNA; Techniques; Testing; Tissues; Tracer; Training; design; diabetes risk; experimental study; fetal; fetus hypoxia; gestational hypoxia; glucose metabolism; glucose production; glucose uptake; in utero; in vivo; in vivo Model; metabolome; metabolomics; novel; oxidation; preference; programs; response; skills; synergism

PROJECT SUMMARY The goal of this proposal is to test the metabolic and molecular effects of hypoxia during late gestation on the early activation of fetal hepatic glucose production rate (GPR). This is important because pregnancies complicated by placental ischemic disease and specifically placental insufficiency induced intrauterine growth restriction (IUGR) expose the fetus to hypoxia. We have shown that the fetal liver during IUGR has increased GPR, which is resistant to suppression by insulin, a hallmark of diabetes pathogenesis. The IUGR fetus also has limited glucose oxidation (GOX) capacity, which may re-direct carbon for GPR. Our published data in the IUGR fetus supports a mechanism whereby FOXO1 increases PCK1 to increase glucose production, and PDK4 to limit glucose oxidation. Importantly, the expression of both PCK1 and PDK4 are inversely related to fetal pO2 indicating that hypoxia is a common regulator of GPR and GOX. Our goal is to understand the hypoxia induced mechanisms for the early activation of fetal GPR. We hypothesize that fetal hypoxia locks FOXO1 into an active nuclear state. This event produces increased PCK1, which increases GPR, and increased PDK4, which decreases GOX to re-direct carbon substrates for GPR and maintain glucose and energy supply for the fetus. I will selectively test the effects of late gestation hypoxia on the fetal liver by precisely reducing fetal arterial pO2 to 11-14 mmHg from 0.8 to 0.9 gestation, which mimics fetal pO2 in age-matched IUGR fetuses. Aim 1 will determine the role of fetal hypoxia in the development of increased GPR and decreased GOX and define novel molecular mechanisms regulating this metabolic adaptation in the fetus. I will measure glucose uptake, utilization, production, and oxidation rates in the alive fetus using metabolic tracer studies. In the fetal liver, I will measure the FOXO1 signaling pathway and expect to identify that hypoxia induces FOXO1 activation to increase PCK1 and PDK4. Coordinated changes in the fetal hepatic metabolome will be determined to support increased carbon substrates for GPR. Aim 2 will determine the fetal hepatocyte substrate preference for GPR and GOX produced by hypoxia. I will measure the oxygen consumption rate of primary fetal hepatocytes to determine if amino acids are preferentially oxidized during hypoxia to compensate for decreased GOX. I will interrogate how hypoxia-induced FOXO1 signaling coordinates GPR and GOX by selectively inducing hypoxia and inhibiting FOXO1. Expected outcomes: Fetal hypoxia will activate GPR and limit GOX through FOXO1 specific mechanisms. Impact: I will define the fetal metabolic and molecular adaptations to hypoxia, which is key to understanding how hypoxia promotes early activation of GPR in the fetal liver, establishing a direct risk for developing type 2 diabetes later in life. The metabolism training plan accompanying these research aims will provide integrative training in metabolic and molecular techniques at the whole-body (fetal), tissue (liver), and cellular (hepatocyte) level to promote my independence as a researcher in fetal metabolism.

项目摘要 该提案的目的是测试晚期妊娠期间缺氧对缺氧的代谢和分子作用对 胎儿肝葡萄糖产生速率（GPR）的早期激活。这很重要，因为怀孕 胎盘缺血性疾病复杂，特别是胎盘不足引起的宫内生长 限制（IUGR）暴露于缺氧。我们已经表明，IUGR期间的胎儿肝脏增加了 GPR，对胰岛素的抑制作用，胰岛素是糖尿病发病机理的标志。 IUGR胎儿也有 有限的葡萄糖氧化（GOX）容量，可能会重新指导GPR的碳。我们在IUGR中发布的数据 胎儿支持FOXO1增加PCK1以增加葡萄糖产生的机制，并限制PDK4 葡萄糖氧化。重要的是，PCK1和PDK4的表达与胎儿PO2成反比 表明缺氧是GPR和GOX的常见调节剂。我们的目标是了解引起的缺氧 胎儿GPR早期激活的机制。我们假设胎儿​​缺氧将FOXO1锁定在一个 活跃的核国家。该事件会产生增加的PCK1，这增加了GPR并增加了PDK4，这 减少GOX以重新指导GPR的碳底物，并维持胎儿的葡萄糖和能量供应。我 将通过精确降低胎儿动脉PO2有选择地测试晚期妊娠缺氧对胎儿肝脏的影响 从0.8到0.9妊娠11-14 mmHg，在年龄匹配的IUGR胎儿中模仿胎儿PO2。目标1意志 确定胎儿缺氧在增加GPR和降低GOX并定义新颖的作用中的作用 分子机制调节胎儿的代谢适应性。我将测量葡萄糖摄取， 使用代谢示踪剂研究，活着胎儿的利用，生产和氧化速率。在胎儿肝中，我会 测量FOXO1信号通路，并期望确定缺氧会诱导FOXO1激活增加 PCK1和PDK4。将确定胎儿肝代谢组的协调变化以支持增加 GPR的碳底物。 AIM 2将确定胎儿肝细胞底物对GPR和GOX的偏好 由缺氧产生。我将测量原发性胎儿肝细胞的氧气消耗率，以确定是否是否 在缺氧期间优先氧化氨基酸，以补偿降低的GOX。我会审问如何 缺氧诱导的FOXO1信号传导通过选择性诱导缺氧并抑制来辅助GPR和GOX FOXO1。预期结果：胎儿缺氧将激活GPR并限制GOX通过FOXO1特异性 机制。影响：我将定义胎儿代谢和分子适应缺氧，这是 了解缺氧如何促进胎儿肝脏中GPR的早期激活，从而建立直接风险 生命后期发展2型糖尿病。这些研究目的伴随的新陈代谢培训计划将 在全身（胎儿），组织（肝）和 细胞（肝细胞）水平，以促进我作为胎儿代谢研究人员的独立性。