Changes in placental thyriod hormone transport associated with maternal obesity

与孕产妇肥胖相关的胎盘甲状腺激素转运的变化

• 批准号: 8633237
• 负责人: Melissa Anne Suter
• 金额: $ 7.45万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633237
• 关键词: Address; Adolescence; Adult; Adverse effects; Adverse event; Amino Acids; Animals; Barker Hypothesis; Binding Proteins; Biological Models; Birth; Birth Weight; Blood Circulation; Body Weight; Cardiovascular Diseases; Cell Line; Cells; Clinical Data; Data; Development; Diabetes Mellitus; Diet; Disease; Environment; Epigenetic Process; Equilibrium; Exhibits; Exposure to; Fatty Acids; Fatty acid glycerol esters; Fetal Development; Fetal Growth; Fetal Liver; Fetus; Genes; Genetic Transcription; Gestational Age; Glucose; Health; Hepatic; Histone Code; Homeostasis; Hormones; Human; Hypertension; Hypothalamic structure; Hypothyroidism; Immunohistochemistry; Individual; Infant; Iodide Peroxidase; Kinetics; Life; Link; Lipids; Lipolysis; Liver; Liver diseases; Measures; Mediator of activation protein; Mentors; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mothers; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Normal Cell; Obesity; Organ; Overweight; Oxidative Stress; Pathology; Perfusion; Perinatal Exposure; Phase; Placenta; Pre-Eclampsia; Pregnancy; Pregnant Women; Prevention; Regulation; Reporting; Research; Risk; Role; Sampling; Serum; Staging; Testing; Therapeutic; Thermogenesis; Third Pregnancy Trimester; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Thyrotropin; Thyroxine; Tissues; Triglycerides; Umbilical Cord Blood; United States; Ursidae Family; Vascular blood supply; Weight; Western Blotting; Woman; base; fatty acid metabolism; fatty acid transport; fetal; fetal blood; glucose transport; histone modification; hormone metabolism; in utero; non-alcoholic fatty liver; nonhuman primate; nutrition; prenatal exposure; prevent; protein expression; public health relevance; receptor; response; thyroid hormone-binding proteins; trophoblast

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.

项目总结/摘要 根据成人健康和疾病的发育起源假说， 使个体在成年期易患代谢综合征。怀孕期间肥胖承担独特的产妇 和胎儿风险，包括胎儿过度生长，产科并发症，以及胎儿 在青春期和成年期出现肥胖和2型糖尿病。然而，分子机制 胎儿过度生长背后的原因尚不清楚。我们在非人类灵长类动物模型中发现， 在子宫内的母亲高脂饮食（MHFD）显示非酒精性脂肪肝疾病的病理， 血清游离脂肪酸和甘油三酯增加，并表现出胎肝组蛋白编码的变化。 此外，我们还发现，在妊娠晚期开始时，暴露于MHFD的胎儿显示出 游离T4（FT 4）显著降低，而母体FT 4保持不变。胎儿甲状腺的这种变化 激素（TH）伴随着脱碘酶基因表达的变化，该基因调节 胎儿肝脏、下丘脑和甲状腺中FT 3和FT 4、TH受体和TH结合蛋白之间的平衡 腺。我们推测，由于母体肥胖引起的胎儿TH稳态的改变可能是分子机制， 胎儿过度生长的介质。甲状腺激素参与调节产热、脂解和 体重母亲和胎儿的TH水平对确定婴儿出生体重都很重要。TH是 对胎儿发育至关重要;胎儿甲状腺在16-20周之间变得活跃之前 怀孕期间，所有必要的TH必须由母亲提供。然而，一旦胎儿甲状腺活跃， 较少的母体TH穿过胎盘。因此，胎盘能够调节母体TH的量 在整个妊娠过程中进入胎儿血液。我们建议研究 胎盘对TH转运和TH代谢的调节与母体肥胖相关，以确定 导致胎儿过度生长的分子机制在这个建议中，我们的目标是测量和分层索 血TH水平由母亲TH水平和母亲BMI。我们假设病态肥胖的胎儿 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FT 4。我们会研究 胎盘TH受体、转运体、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qPCR从瘦和肥胖女性中分离。利用培养的原代滋养层细胞 我们将测试来自瘦和肥胖妇女胎盘的细胞转录和表观遗传， 使用微阵列和ChIP-Seq.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，以研究胎盘组织中氨基酸、脂肪酸和葡萄糖转运的变化。 不同数量的TH的存在。结合起来，这些研究将不仅提供有关作用的信息， TH在胎儿过度生长中的作用，但可能提供一种治疗机制， 即使是有持续肥胖的母亲。