Changes in placental thyriod hormone transport associated with maternal obesity

项目摘要/摘要 根据发育起源的成人健康和疾病假说，子宫中的不良暴露 使一个人在成年后易患代谢综合征。孕期肥胖具有独特的母性 和胎儿风险，包括胎儿过度生长，产科并发症，以及胎儿发生 在青春期和成年期患肥胖症和2型糖尿病。然而，分子机制 胎儿过度生长的原因尚不清楚。我们发现在我们的非人类灵长类动物模型中，胎儿暴露在 宫内高脂饮食(MHFD)表现为非酒精性脂肪性肝病的病理基础，有 增加血清游离脂肪酸和甘油三酯，并表现出胎儿肝组蛋白密码的变化。 此外，我们还发现，在妊娠晚期，暴露于MHFD的胎儿表现出 游离T4(FT4)显著下降，而母体FT4无明显变化。胎儿甲状腺的这种变化 荷尔蒙(TH)伴随着脱碘酶基因表达的变化，该基因调节 胎肝、下丘脑和甲状腺中FT3和FT4、TH受体和TH结合蛋白的平衡 腺体。我们假设母体肥胖引起的胎儿TH稳态的改变可能是分子的。 胎儿过度生长的调节因子。甲状腺激素参与产热、脂肪分解和 体重。孕妇和胎儿的TH水平对确定婴儿出生体重都很重要。这是 对胎儿发育至关重要的；在胎儿甲状腺在16-20周之间变得活跃之前 怀孕时，所有必要的东西都必须由母亲提供。然而，一旦胎儿甲状腺活跃起来， 较少母体的TH穿过胎盘。因此，胎盘能够调节母体Th的量。 在整个怀孕过程中进入胎儿血液。我们建议研究 胎盘调节TH转运和TH代谢与母亲肥胖相关 胎儿过度生长的分子机制。在本提案中，我们的目标是测量和分层绳索 按母体TH水平和母体BMI计算的血TH水平。我们假设病态肥胖症的胎儿 母亲将患有亚临床甲状腺功能减退症，表现为高TSH水平和低FT4水平。我们将研究 胎盘中TH受体、转运蛋白、结合蛋白和脱碘酶基因的丰度和定位 使用免疫组织化学和定量聚合酶链式反应检测瘦身和肥胖女性。利用培养的原代滋养层细胞 取自瘦身和肥胖女性的胎盘，我们将测试细胞转录和表观遗传学 利用微阵列和芯片序列对TH的响应。此外，我们建议使用永生化滋养层细胞作为 以及胎盘灌流模型，研究胎盘中氨基酸、脂肪酸和葡萄糖转运的变化。 不同数量的TH的存在。总而言之，这些研究不仅将提供有关角色的信息 TH在胎儿过度生长中的作用，但可能提供一种靶向和预防过度生长的治疗机制 即使是持续的母体肥胖。

Project Summary/Abstract According to the developmental origins of adult health and disease hypothesis, adverse in utero exposures predispose an individual to metabolic syndrome in adulthood. Obesity during pregnancy bears unique maternal and fetal risks, including fetal overgrowth, obstetrical complications, and an increased risk for the fetus to develop obesity and type 2 diabetes in adolescence and adulthood. However, the molecular mechanisms behind fetal overgrowth remain unclear. We have found in our non-human primate model that fetuses exposed in utero to maternal high fat diet (MHFD) show the pathology of non-alcoholic fatty liver disease, have increased serum free fatty acids and triglycerides, and exhibit changes in the fetal hepatic histone code. Furthermore, we have found at the beginning of the third trimester, fetuses exposed to a MHFD show a significant decrease in free T4 (FT4) while maternal FT4 remains unchanged. This change in fetal thyroid hormone (TH) is accompanied by changes in the expression of the deiodinase genes which regulate the balance between FT3 and FT4, TH receptors, and TH binding proteins in fetal liver, hypothalamus and thyroid gland. We hypothesize that alterations in fetal TH homeostasis due to maternal obesity are likely molecular mediators of fetal overgrowth. Thyroid hormones are involved in the regulation of thermogenesis, lipolysis, and body weight. Both maternal and fetal TH levels are important for determining infant birth weight. THs are essential for fetal development; before the fetal thyroid gland becomes active between 16-20 weeks of gestation, all necessary THs must be provided by the mother. However once the fetal thyroid gland is active, less maternal TH crosses the placenta. Therefore the placenta is able to regulate the amount of maternal THs which enter the fetal bloodstream throughout the course of gestation. We propose to study changes in the placental regulation of TH transport and TH metabolism associated with maternal obesity to determine a molecular mechanism contributing to fetal overgrowth. In this proposal we aim to measure and stratify cord blood TH levels by maternal TH levels and maternal BMI. We hypothesize that fetuses of morbidly obese mothers will have subclinical hypothyroidism showing high TSH levels and low FT4. We will examine the abundance and localization of TH receptors, transporters, binding proteins and deiodinase genes in placentas from lean and obese women using immunohistochemistry and qPCR. Using cultured primary trophoblast cells derived from placentas from lean and obese women we will test the cellular transcriptional and epigenetic response to TH using microarray and ChIP-Seq. Furthermore, we propose to use immortalized trophoblasts as well as the placental perfusion model to study the changes in amino acid, fatty acid and glucose transport in the presence of differing quantities of TH. Combined, these studies will not only provide information on the role of TH in fetal overgrowth but may offer a therapeutic mechanism by which to target and prevent overgrowth even with persistent maternal obesity.