Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health

修改后的项目摘要/摘要部分 遗传因素和环境因素都是2型糖尿病(T2D)发生的原因。高胰岛素血症通常见于患有糖尿病前期、肥胖和妊娠期糖尿病的孕妇，她们的后代患T2D的风险更大。然而，目前还没有研究解决当母亲高胰岛素血症时后代的长期/纵向代谢结果。此外，母体高胰岛素血症与子代代谢性疾病之间的机制联系在很大程度上仍不清楚。人们的信条是，胰岛素不会通过胎盘进入胎儿来调节胎儿的生长。然而，母体胰岛素可以作为一种生长因子和一种与胎盘胰岛素受体(IR)和胰岛素样生长因子1受体(IGF1R)结合的合成激素来驱动关键的胎盘功能，包括向胎儿输送营养物质。因此，母体胰岛素可以通过改变胎儿代谢组织的营养可获得性来改变胎盘功能，从而导致永久性的变化，使后代在成年后易患T2D。事实上，我们有令人信服的初步数据显示，高胰岛素血症母鼠的后代体重增加，葡萄糖耐量增加。我们发现胎盘特异性IR缺失在改善高胰岛素血症母鼠后代的糖耐量方面有良好的效果。这些观察提供了一个强有力的前提，即胎盘整合了母体高胰岛素血症信号和胎盘营养流向生长中的胎儿，从而规划了后代的代谢健康。在这项授权中，我们将检验主要假设，即母亲高胰岛素血症导致的后代体重增加和糖耐量增加是由于胎盘营养流向胎儿的增加所致，胎盘中IR和IGF1R信号及其下游靶点mTOR和GLUT4的增加介导了这一过程。为了验证这一假设，我们开发了带有或不带有胎盘IR或IGF1R缺失的母亲高胰岛素血症的新的创新模型，以利用并获得在纵向队列子代中代谢和生理研究的详细体内机制方法。在目标1中，我们将通过对妊娠期母体高胰岛素血症的临床前遗传模型的功能研究，确定长期的代谢结果和信号机制，从而调节子代的代谢健康。在目标2中，我们将确定有或没有胎盘特异性胰岛素信号或GLUT4缺乏的后代的母婴营养通量。这些机制研究具有非常重要的意义，因为它们将确定母亲高胰岛素血症影响代谢健康的分子机制，并强调在怀孕期间临床控制胰岛素水平的重要性，类似于葡萄糖，以改善妊娠结局。因此，该项目的预期成功将对改善妇女的生殖健康和后代的代谢健康产生重大影响。

Modified Project Summary/Abstract Section Both genetic and environmental factors contribute to the development of Type 2 diabetes (T2D). Hyperinsulinemia is commonly seen among pregnant women with prediabetes, obesity, and gestational diabetes, and their offspring has a greater risk for developing T2D. Yet, no current study addresses the long-term/longitudinal metabolic outcomes of the offspring when the mother is hyperinsulinemic. Furthermore, the mechanistic link between maternal hyperinsulinemia and the programming of metabolic disease in the offspring remains largely unknown. The dogma is that insulin does not cross the placenta into the fetus to regulate fetal growth. However, maternal insulin can act as a growth factor and an anabolic hormone binding to the placental insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) to drive critical placental function, including nutrient flux to the fetus. Thus, maternal insulin can change placental function by altering nutrient availability to fetal metabolic tissues causing permanent changes that predispose the offspring to T2D in adulthood. Indeed, we have compelling preliminary data showing increased body weight and glucose intolerance in the offspring of hyperinsulinemic dams. We identified that placental-specific IR deletion has a beneficial effect in improving glucose tolerance in the offspring of hyperinsulinemic dams. These observations provide a strong premise that the placenta integrates maternal hyperinsulinemia signals with placental nutrient flux to the growing fetus, thereby programming the metabolic health of the offspring. In this grant, we will test the main hypothesis that the increased body weight and glucose intolerance programming in the offspring by maternal hyperinsulinemia is caused by increased placental nutrient flux to the fetus, which is mediated by increased IR and IGF1R signaling and their downstream targets, mTOR and GLUT4, in the placenta. To test this hypothesis, we developed new innovative models of maternal hyperinsulinemia with or without placental IR or IGF1R deletion, to leverage and obtain a detailed in vivo mechanistic approach of metabolic and physiological studies in a longitudinal cohort of offspring. In Aim 1, we will define long-term metabolic outcomes and signaling mechanisms whereby maternal hyperinsulinemia regulates metabolic health of the offspring using functional studies with preclinical genetic models of maternal hyperinsulinemia during pregnancy with or without placenta-specific loss of IR, IGF1R, IR/IGF1R compound or mTOR. In Aim 2, we will determine maternal-to-fetal nutrient flux in the offspring with or without placenta-specific insulin-signaling or GLUT4 deficiencies. These mechanistic studies are highly significant because they will define the molecular mechanisms whereby maternal hyperinsulinemia impacts metabolic health, and they underscore the importance of clinically controlling insulin levels during pregnancy, similar to glucose, to improve pregnancy outcomes. Thus, the anticipated success of this project will have significant implications in improving women’s reproductive health and the metabolic health of the offspring.