Regulation of Maternal Fuel Supply and Neonatal Adiposity

越来越多的流行病学证据表明，母亲肥胖和妊娠期糖尿病（GDM） 独立地影响出生时的大小和以后生活中的疾病易感性。我们在理解上的一个主要差距是 胎儿编程的知识是否以及如何暴露于过量的母体燃料， 明显的高血糖影响胎儿脂肪的增加。我们的假设是新生儿肥胖和胰岛素 抵抗是由于未被认识到的母体高血糖和妊娠期过量脂质可用性， 部分原因是肥胖女性较早从脂肪生成转变为脂解。在目标1中，我们将使用稳定 同位素技术测定空腹和胰岛素抑制状态下母体甘油周转率， 液体餐以评估餐后TG波动，呼吸气体交换以测量脂质， 碳水化合物氧化，DXA确定身体成分，以及早期和长期血糖监测 瘦型、肥胖型和GDM受试者的妊娠晚期。在目标2中，我们将测试新生儿 DXA测定的肥胖与肥胖者的过量脂质和葡萄糖利用率密切相关。 在妊娠早期表现出这两种异常的患有或不患有GDM的母亲。而且我们 将测试新生儿胰岛素敏感性的假设，通过口服葡萄糖耐量试验评估， 心血管风险标志物至少可以部分地通过胎儿和/或新生儿肥胖来预测。在目标3 我们将把全身脂解的变化与母体脂肪组织的分子差异联系起来， 瘦的和肥胖的孕妇。我们实验室的证据表明人类胎盘的生长 激素导致两种分子PPARg和脂联素的功能抑制，其活性是 维持胰岛素敏感性所需的。我们预测肥胖女性的胰岛素分泌 抵抗更早或更深刻，从而加速脂肪分解，使多余的FFA和葡萄糖更多， 胎儿-胎盘单位容易获得。我们将对比脂肪细胞标志物的差异， 分化/功能，包括细胞大小分布、脂联素分泌和胰岛素信号传导，以及 在早期和晚期获得的来自瘦、肥胖和GDM妇女的脂肪细胞中的脂解抑制 怀孕阐明葡萄糖和脂质代谢中的特定紊乱及其发生时间 在妊娠期，分娩过胖婴儿的母亲可能会挑战我们目前的筛查 方法和完全重新定向我们的治疗，以针对负责任的母亲燃料。关于公共卫生 水平，这项研究有助于我们了解子宫内环境如何可能提供 过量的葡萄糖和/或脂质输送给胎儿，并导致儿童肥胖症流行的发生。 这些信息可能会导致新的治疗策略，在孕妇正常胎儿生长。

Mounting epidemiological evidence suggests that maternal obesity and Gestational Diabetes Mellitus (GDM) independently influence size at birth and disease susceptibility later in life. A major gap in our understanding of fetal programming is knowledge of whether and how exposure to excess maternal fuels in the absence of frank hyperglycemia impacts fetal fat accretion. Our hypothesis is that neonatal adiposity and insulin resistance result from unrecognized maternal hyperglycemia and excess lipid availability in pregnancy, in part due to an earlier switch from adipogenesis to lipolysis in obese women. In Aim 1 we will utilize stable isotope technology to determine maternal glycerol turnover in the fasted and insulin suppressed state, a liquid meal to assess postprandial TG excursions, respiratory gas exchange to measure lipid and carbohydrate oxidation, DXA to determine body composition, and continuous glucose monitoring both early and late in pregnancy in lean, obese, and GDM subjects. In Aim 2, we will test the hypothesis that neonatal adiposity determined by DXA are strongly correlated with excess lipid and glucose availability in obese mothers with and without GDM who manifest both of these abnormalities early in gestation. Furthermore, we will test the hypothesis that neonatal insulin sensitivity, as assessed by oral glucose tolerance tests and cardiovascular risk markers, can at least be partially predicted by fetal and/or neonatal adiposity. In Aim 3 we will relate changes in total body lipolysis to molecular differences in maternal adipose tissue between lean and obese pregnant women. Evidence from our laboratories indicates that human placental growth hormone leads to a functional inhibition of two molecules, PPARg and adiponectin, whose activities are required for the maintenance of insulin sensitivity. We predict that in obese women this switch to insulin resistance is earlier or more profound, thereby accelerating lipolysis making excess FFA and glucose more readily available to the fetal-placental unit. We will contrast the differences in markers of adipocyte differentiation/function including cell size distribution, adiponectin secretion, and insulin signaling and suppression of lipolysis in adipocytes from lean, obese and GDM women obtained in early and late pregnancy. The elucidation of specific derangements in both glucose and lipid metabolism and their timing in gestation in mothers who deliver infants with excess adiposity could challenge our current screening methods and entirely redirect our treatment to target the responsible maternal fuels. On a public health level, this research is instrumental to our understanding of how an intrauterine environment may deliver excess glucose and/or lipids to the fetus and contribute to the genesis of the pediatric obesity epidemic. Such information may result in new treatment strategies in pregnant women to normalize fetal growth.