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）独立影响出生时的大小和以后生活中的疾病易感性。我们对胎儿编程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堆积的知识。我们的假设是，新生儿肥胖和胰岛素抵抗是由未被认识到的母体高血糖和怀孕期间过量的脂质供应引起的，部分原因是肥胖女性从脂肪生成早期转变为脂肪分解。在目标1中，我们将利用稳定同位素技术确定空腹和胰岛素抑制状态下的母体甘油周转率，利用液体餐评估餐后TG波动，利用呼吸气体交换测量脂质和碳水化合物氧化，利用DXA确定身体成分，并在妊娠早期和晚期对瘦型、肥胖和GDM受试者进行连续葡萄糖监测。在目标2中，我们将测试的假设，DXA确定的新生儿肥胖与过量的脂质和葡萄糖的可用性在肥胖的母亲和没有GDM谁表现出这两个异常妊娠早期密切相关。此外，我们将测试的假设，新生儿胰岛素敏感性，通过口服葡萄糖耐量试验和心血管危险标志物评估，可以至少部分预测胎儿和/或新生儿肥胖。在目标3中，我们将把全身脂解的变化与瘦型和肥胖型孕妇之间母体脂肪组织的分子差异联系起来。来自我们实验室的证据表明，人胎盘生长激素导致两种分子PPARg和脂联素的功能抑制，这两种分子的活性是维持胰岛素敏感性所必需的。我们预测，在肥胖妇女中，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FFA和葡萄糖更容易被胎儿胎盘单位利用。我们将对比脂肪细胞分化/功能的标志物的差异，包括细胞大小分布，脂联素分泌，胰岛素信号和脂肪细胞的脂解抑制从瘦，肥胖和GDM妇女在怀孕早期和晚期获得。阐明在分娩肥胖婴儿的母亲中，葡萄糖和脂质代谢的特定紊乱及其妊娠时间可能会挑战我们目前的筛查方法，并完全将我们的治疗重新定向为针对负责任的母体燃料。在公共卫生层面上，这项研究有助于我们了解宫内环境如何向胎儿提供过量的葡萄糖和/或脂质，并有助于儿童肥胖流行病的发生。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.