Regulation of Maternal Fuel Supply and Neonatal Adiposity

母体燃料供应和新生儿肥胖的调节

• 批准号: 7492974
• 负责人: LINDA Anne BARBOUR
• 金额: $ 16.05万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492974
• 关键词: Adipocytes; Adipose tissue; Birth; Body Composition; Carbohydrates; Cell Size; Childhood; Disease susceptibility; Dual-Energy X-Ray Absorptiometry; Environment; Epidemic; Exposure to; Fasting; Fatty acid glycerol esters; Fetal Growth; Fetus; Gestational Diabetes; Glucose; Glycerol; Human; Hyperglycemia; Infant; Insulin; Insulin Resistance; Knowledge; Laboratories; Life; Lipids; Lipolysis; Liquid substance; Maintenance; Measures; Methods; Molecular; Mothers; Neonatal; OGTT; Obesity; Pregnancy; Pregnant Women; Public Health; Regulation; Research; Risk Marker; Screening procedure; Technology; Testing; Time; Woman; adipocyte differentiation; adiponectin; cardiovascular risk factor; fetal; fetal programming; glucose monitor; human HGH-V protein; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; oxidation; respiratory gas; size; stable isotope

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.

越来越多的流行病学证据表明，孕产妇肥胖和妊娠糖尿病（GDM）独立影响出生时大小和生命后期的疾病敏感性。我们对胎儿编程的理解的一个主要差距是了解在没有弗兰克高血糖的情况下是否以及如何暴露于过量的母体燃料会影响胎儿脂肪的积聚。我们的假设是，新生儿肥胖性和胰岛素抵抗是由于未识别的母体高血糖和怀孕期间过量的脂质供应而引起的，部分原因是肥胖女性的脂肪形成转变为脂解。在AIM 1中，我们将利用稳定的同位素技术来确定禁食和胰岛素抑制状态的母体甘油的转换，一种液体餐，评估餐后TG偏移，呼吸气交换来测量脂质和碳水化合物氧化，DXA，DXA，DXA，以确定身体成分和连续的Gluc gluc comporte in Pregand and Neard in Pregine in Pregine in Pregine in Pregine in Pregine in Phime in preansy in Phimess in limes in，均为肥胖症，肥胖。在AIM 2中，我们将检验以下假设：DXA确定的新生儿肥胖与患有和没有GDM的肥胖母亲的脂质和葡萄糖可用性密切相关，而GDM和没有GDM的GDM表现出了这两种异常。此外，我们将检验以下假设：通过口服葡萄糖耐量测试和心血管危险标志物评估，新生儿胰岛素敏感性至少可以通过胎儿和/或新生儿肥胖来预测。在AIM 3中，我们将将全身脂解的变化与瘦孕妇和肥胖孕妇之间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，人胎盘生长激素会导致对两个分子PPARG和脂联素的功能抑制，它们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，这种转向胰岛素抵抗的转变更早或更深刻，从而加速脂肪，从而使胎儿 - 置换单元更容易获得过多的FFA和葡萄糖。我们将对比脂肪细胞分化/功能标记的差异，包括细胞大小分布，脂联素分泌，胰岛素信号传导以及在早期和晚期获得的瘦肉，肥胖和GDM妇女的脂肪细胞中脂肪分解的抑制。在葡萄糖和脂质代谢中阐明特定的危险及其在妊娠中的时机及其在妊娠中的时机，这些母亲的妊娠期肥胖可能会挑战我们当前的筛查方法，并完全将我们的治疗方法重新定向以瞄准负责任的母体燃料。在公共卫生层面上，这项研究对我们对宫内环境如何向胎儿提供过量的葡萄糖和/或脂质的理解至关重要，并有助于小儿肥胖症的起源。这些信息可能会导致孕妇的新治疗策略使胎儿生长正常化。