Regulation of Maternal Fuel Supply and Neonatal Adiposity

越来越多的流行病学证据表明，产妇肥胖和妊娠期糖尿病（GDM）独立影响出生时的体型和以后生活中的疾病易感性。我们对胎儿计划的理解的一个主要差距是在没有明显高血糖的情况下暴露于过量的母体燃料是否以及如何影响胎儿脂肪增加的知识。我们的假设是，新生儿肥胖和胰岛素抵抗是由于孕期未被认识到的母体高血糖和脂质可利用性过高，部分原因是肥胖女性较早地从脂肪生成转变为脂肪分解。在Aim 1中，我们将利用稳定同位素技术测定孕妇在禁食和胰岛素抑制状态下的甘油转换，利用液体餐评估餐后TG漂移，呼吸气体交换测量脂质和碳水化合物氧化，DXA测定身体成分，并在瘦、肥胖和GDM受试者的妊娠早期和晚期持续监测葡萄糖。在Aim 2中，我们将检验由DXA确定的新生儿肥胖与妊娠早期表现出这两种异常的有或无GDM的肥胖母亲的过量脂质和葡萄糖可用性密切相关的假设。此外，我们将验证通过口服葡萄糖耐量试验和心血管危险标志物评估的新生儿胰岛素敏感性至少可以部分由胎儿和/或新生儿肥胖预测的假设。在Aim 3中，我们将把全身脂肪分解的变化与瘦孕妇和肥胖孕妇母体脂肪组织的分子差异联系起来。我们实验室的证据表明，人类胎盘生长激素导致PPARg和脂联素两个分子的功能抑制，这两个分子的活性是维持胰岛素敏感性所必需的。我们预测，在肥胖女性中，这种胰岛素抵抗的转变更早或更深刻，从而加速脂肪分解，使多余的游离脂肪酸和葡萄糖更容易被胎儿-胎盘单位获得。我们将对比在妊娠早期和晚期获得的瘦、肥胖和GDM女性脂肪细胞分化/功能标志物的差异，包括细胞大小分布、脂联素分泌、胰岛素信号和脂肪细胞中脂肪分解的抑制。对妊娠期过度肥胖婴儿的母亲的糖脂代谢的特定紊乱及其时间的阐明，可能会挑战我们目前的筛查方法，并完全改变我们的治疗方向，以针对负责任的母亲燃料。在公共健康层面上，这项研究有助于我们理解宫内环境如何向胎儿输送过量的葡萄糖和/或脂质，并有助于儿童肥胖流行的起源。这些信息可能会导致新的治疗策略，使孕妇的胎儿生长正常化。

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.