Biomarkers of materno-fetal health: role placental endocrine mediators in normal and obese pregnancies

怀孕期间肥胖会影响孕妇和婴儿在怀孕期间和之后很长一段时间的健康。它增加了孕妇在怀孕期间患糖尿病等健康并发症的风险，也增加了母亲在分娩后几年患2型糖尿病的易感性。它还导致婴儿出现一系列新生儿和以后生活健康并发症，使婴儿在以后的生活中更容易患上代谢疾病。尽管如此，导致肥胖妇女怀孕期间不良妊娠结局的机制仍不清楚。胎盘是产生激素的器官，负责改变母亲的新陈代谢，以确保胎儿在怀孕期间有足够的营养。然而，迄今为止，在母亲肥胖的怀孕中，胎盘激素的产生在母体代谢并发症的发展中或在后代不良健康结果的规划中所起的作用知之甚少。因此，本研究旨在确定在母亲肥胖的怀孕中，胎盘激素产生对母亲代谢、胎儿生长和后代代谢健康的重要性。这将通过在怀孕前或怀孕期间给雌性小鼠喂食高糖和高脂肪的饮食来实现，从而导致妊娠期间的肥胖和/或代谢功能障碍。母亲利用葡萄糖和对胰岛素（通常调节葡萄糖代谢）作出反应的能力，将在怀孕期间在胎盘中有或没有破坏胎盘激素产生的遗传缺陷的小鼠中进行研究。母鼠的新陈代谢与幼崽出生前后的生长发育有关，也与幼崽成年后的代谢健康有关。此外，将使用最新的测序方法测量胎盘在母亲体内产生具有代谢作用的激素的能力，以确定导致肥胖和/或代谢功能障碍小鼠不良妊娠结局的激素。胎盘激素在小鼠妊娠期母体代谢失调中起着重要作用，随后将在妊娠期间代谢正常或患有糖尿病的瘦弱和肥胖女性的胎盘和血液中进行测量，以确定它们是否也能预测人类的妊娠结局。该项目将为科学家和临床医生提供有关肥胖妇女及其子女妊娠并发症和代谢疾病原因的新信息。它将确定胎盘如何与母亲沟通，从而影响肥胖孕妇的胎儿营养和生长，并最终影响生命质量，以及在长期内出现缩短寿命的代谢疾病的风险。预期这项工作将确定胎盘分泌的关键激素，这些激素负责妊娠并发症和肥胖妇女及其家庭代谢疾病的相关程序。此外，这些胎盘激素在母亲体内的水平可能是她和她的孩子在怀孕期间健康状况的早期指标，这可能最终用于诊断和开发治疗方法，以防止肥胖妇女的不良妊娠结果。这样，拟议的项目就有能力减轻目前肥胖流行病对卫生保健系统的负担。

Obesity during pregnancy affects maternal and infant health both during pregnancy and for long afterwards. It raises the risk of health complications like maternal diabetes during pregnancy, as well as, increases the susceptibility of the mother to develop type-2 diabetes in the years after delivery. It also leads to a range of neonatal and later life health complications in their infants, such that infants are more prone to develop metabolic diseases themselves in later life. Despite this, the mechanisms operating during pregnancy that lead to these poor pregnancy outcomes in obese women, remain unknown. The placenta is the organ that produces hormones responsible for changing the metabolism of the mother to ensure sufficient nutrients are available for fetal growth during pregnancy. However, to date, little is known about the role of placental hormone production in the development of maternal metabolic complications or in the programming of poor health outcomes of the offspring, in pregnancies where the mother is obese. Thus, this study aims to identify the importance of placental hormone production for maternal metabolism, fetal growth and offspring metabolic health, in pregnancies where the mother is obese. This will be achieved by feeding female mice from before pregnancy or only during pregnancy, a diet high in sugar and fat to cause obesity and/or metabolic dysfunction during gestation. The mother's ability to use glucose and respond to insulin, which normally regulates glucose metabolism, will then be studied during pregnancy in mice with and without a genetic defect in the placenta that disrupts placental hormone production. The metabolism of the mother will be related to growth of their pups before and after birth, as well as, to pup metabolic health in adult life. In addition, the capacity of the placenta to produce hormones with metabolic effects in the mother will be measured using the latest sequencing methods to identify the hormones responsible for the adverse pregnancy outcomes in mice that are obese and/or with metabolic dysfunction. Placental hormones identified to be important in the dysregulation of maternal metabolism in mouse pregnancies, will then be measured in the placenta and blood of lean and obese women with normal metabolism or diabetes during pregnancy to establish whether they too predict pregnancy outcome in humans. The project will provide both scientists and clinical doctors with novel information on the cause of pregnancy complications and metabolic diseases in obese women and their children. It will identify how the placenta communicates with the mother to influence fetal nutrition and growth in obese pregnancies, and ultimately, the quality of life and subsequent risk of developing life-shortening metabolic conditions in the longer term. The anticipation is that this work will identify critical hormones secreted by placenta that are responsible for the pregnancy complications and the associated programming of metabolic diseases in obese women and their families. Also, that the levels of these placental hormones in the mother may serve as early indicators of her well-being and that of her baby during pregnancy, which could be ultimately used to diagnose and develop therapies to prevent adverse pregnancy outcomes in obese women. In doing so, the proposed project has the capacity to reduce the burden of the current obesity epidemic, on the health care system.