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.
Obesity during pregnancy bears unique risks to both the mother and the fetus, including fetal overgrowth, obstetrical complications, and an increased risk of adult metabolic disease for the exposed fetus. While the molecular mechanisms behind this fetal overgrowth remain unclear, data from our well established non-human primate model of maternal obesity indicates thyroid hormones as likely molecular mediators. The research outlined in this proposal aims to study thyroid hormone specific changes in the placenta associated with maternal obesity in order to increase our understanding of the adverse effects of prenatal exposure to maternal over nutrition.
