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的生活中的疾病易感性。我们在认识上的一个重大差距 胎儿计划的关键是了解是否以及如何在没有胎儿营养的情况下暴露于过量的母亲燃料 弗兰克高血糖影响胎儿脂肪堆积。我们的假设是新生儿肥胖和胰岛素 抵抗是由于未被识别的母亲高血糖和怀孕期间过量的脂肪供应所致 部分原因是肥胖女性较早地从脂肪生成转换为脂肪分解。在目标1中，我们将使用稳定的 用同位素技术测定禁食和胰岛素抑制状态下的母体甘油周转 液体餐用于评估餐后TG漂移，呼吸气体交换用于测量血脂和 碳水化合物氧化，DXA来确定身体成分，以及早期的连续血糖监测 瘦子、肥胖者和妊娠期糖尿病受试者在怀孕后期。在目标2中，我们将检验新生儿 DXA测定的肥胖症与肥胖者过多的脂肪和葡萄糖供应密切相关 患有和不患有妊娠期糖尿病的母亲在怀孕早期都表现出这两种异常。此外，我们 将检验通过口服葡萄糖耐量试验评估的新生儿胰岛素敏感性和 心血管危险标记物，至少可以部分预测胎儿和/或新生儿肥胖。在AIM 3中 我们将把全身脂肪分解的变化与母体脂肪组织的分子差异联系起来。 瘦身和肥胖的孕妇。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，在肥胖的女性中，这种转变为胰岛素 抵抗力更早或更严重，从而加速脂肪分解，使过量的FFA和葡萄糖 对胎儿-胎盘单位来说很容易获得。我们将比较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转导。 早期和晚期瘦身、肥胖和妊娠期糖尿病患者脂肪细胞中脂肪分解的抑制 怀孕了。糖脂代谢特殊紊乱的阐明及其发生的时间 在孕期分娩过度肥胖婴儿的母亲可能会挑战我们目前的筛查 方法，并完全重新定向我们的治疗目标，以负责任的母亲燃料。关于公共卫生 这项研究有助于我们理解宫内环境是如何分娩的 过量的葡萄糖和/或脂肪会对胎儿造成伤害，并导致儿童肥胖症流行。 这些信息可能会导致孕妇采取新的治疗策略，以使胎儿发育正常。

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.