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: 8796207
• 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/8796207
• 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; ChIP-seq; 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; Hormone use; 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; receptor; response; thyroid hormone-binding proteins; trophoblast

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：根据成人健康和疾病的发育起源假说，子宫中的不良暴露使个人在成年后易患代谢综合征。妊娠期肥胖具有独特的母婴风险，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患肥胖症和2型糖尿病的风险增加。然而，胎儿过度生长背后的分子机制仍不清楚。在我们的非人灵长类动物模型中，我们发现在宫内暴露于母体高脂饮食(MHFD)的胎儿表现出非酒精性脂肪性肝病的病理，血清游离脂肪酸和甘油三酯增加，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的胎儿游离T4(FT4)显著下降，而母亲FT4保持不变。胎儿甲状腺激素(TH)的这种变化伴随着胎儿肝脏、下丘脑和甲状腺中调节FT3和FT4之间平衡的脱碘酶基因、TH受体和TH结合蛋白的表达的变化。我们推测，母体肥胖引起的胎儿TH稳态的改变可能是胎儿过度生长的分子介质。甲状腺激素参与产热、脂肪分解和体重的调节。孕妇和胎儿的TH水平对确定婴儿出生体重都很重要。这对胎儿的发育是必不可少的；在怀孕16-20周之间胎儿甲状腺开始活跃之前，必须由母亲提供所有必要的营养。然而，一旦胎儿甲状腺活跃，母体TH穿过胎盘的次数就会减少。因此，在整个妊娠过程中，胎盘能够调节进入胎儿血液的母体TH的量。我们建议研究与母亲肥胖相关的胎盘TH运输和TH代谢的变化，以确定导致胎儿过度生长的分子机制。在这项建议中，我们的目标是通过母体TH水平和母体BMI来测量和分层脐血TH水平。我们假设，病态肥胖母亲的胎儿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。我们将利用免疫组织化学和定量聚合酶链式反应检测瘦身和肥胖妇女胎盘中TH受体、转运体、结合蛋白和脱碘酶基因的丰度和定位。利用从瘦身和肥胖妇女胎盘中提取的原代滋养层细胞，我们将使用基因芯片和芯片序列来检测细胞对TH的转录和表观遗传学反应。此外，我们建议使用永生化滋养层细胞以及胎盘灌流模型来研究不同数量TH存在时氨基酸、脂肪酸和葡萄糖转运的变化。总而言之，这些研究不仅将提供关于TH在胎儿过度生长中所起作用的信息，而且可能提供一种治疗机制，通过该机制即使在持续存在母体肥胖的情况下也可以靶向和预防过度生长。