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，母亲肥胖和妊娠期糖尿病(GDM)独立地影响出生时的体型和晚年的疾病易感性。在我们对胎儿计划的理解中，一个主要的差距是了解在没有明显的高血糖的情况下，暴露于过量的母体燃料是否以及如何影响胎儿脂肪的积累。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脂肪供应过剩造成的，部分原因是肥胖女性较早从脂肪生成转换为脂肪分解。在目标1中，我们将利用稳定同位素技术来测定禁食和胰岛素抑制状态下的母体甘油周转，用液体餐来评估餐后甘油三酯的漂移，用呼吸气体交换来测量脂肪和碳水化合物的氧化，用DXA来确定身体成分，以及在妊娠早期和晚期持续监测瘦身、肥胖和妊娠期糖尿病受试者。在目标2中，我们将检验这样一种假设，即DXA确定的新生儿肥胖与肥胖母亲中过量的脂肪和葡萄糖供应密切相关，无论是否患有GDM，这些母亲在怀孕早期都表现出这两种异常。此外，我们将检验这样一种假设，即通过口服葡萄糖耐量试验和心血管风险标记物评估的新生儿胰岛素敏感性至少可以通过胎儿和/或新生儿肥胖来部分预测。在目标3中，我们将把全身脂肪分解的变化与瘦身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，这种向胰岛素抵抗的转变更早或更严重，从而加速脂肪分解，使多余的FFA和葡萄糖更容易被胎儿-胎盘单位获得。我们将比较早孕和晚孕妇女脂肪细胞分化/功能指标的差异，包括细胞大小分布、脂联素分泌、胰岛素信号和脂肪分解抑制。在分娩婴儿过度肥胖的母亲中，阐明糖和脂代谢的特定紊乱及其在怀孕期间的时机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，将目标对准负责的母亲燃料。在公共卫生层面上，这项研究有助于我们理解宫内环境如何将过量的葡萄糖和/或脂肪输送到胎儿，并有助于儿童肥胖流行的发生。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。