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）独立影响出生时的体型和以后的疾病易感性。我们对胎儿编程理解的一个主要差距是了解在没有明显高血糖的情况下暴露于过量母体燃料是否以及如何影响胎儿脂肪增加。我们的假设是，新生儿肥胖和胰岛素抵抗是由未被识别的母体高血糖和妊娠期脂质过多造成的，部分原因是肥胖女性较早地从脂肪生成转变为脂肪分解。在目标 1 中，我们将利用稳定同位素技术来确定禁食和胰岛素抑制状态下的母体甘油周转率，利用流质膳食来评估餐后 TG 偏移，利用呼吸气体交换来测量脂质和碳水化合物氧化，利用 DXA 来确定身体成分以及持续血糖监测瘦、肥胖和 GDM 受试者的妊娠早期和晚期。在目标 2 中，我们将检验以下假设：在患有或不患有 GDM 的肥胖母亲中，DXA 确定的新生儿肥胖与过量的脂质和葡萄糖可用性密切相关，这些母亲在妊娠早期就表现出这两种异常。此外，我们将检验这样的假设：通过口服葡萄糖耐量试验和心血管风险标志物评估的新生儿胰岛素敏感性至少可以部分地通过胎儿和/或新生儿肥胖来预测。在目标 3 中，我们将把全身脂肪分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 PPARg 和脂联素这两种分子的功能性抑制，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，在肥胖女性中，这种向胰岛素抵抗的转变会更早或更严重，从而加速脂肪分解，使过量的 FFA 和葡萄糖更容易被胎儿胎盘单位利用。我们将对比妊娠早期和晚期的瘦、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、胰岛素信号传导和脂肪分解抑制。阐明产下肥胖婴儿的母亲的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，并完全改变我们的治疗目标，以负责任的母亲能量为目标。在公共卫生层面上，这项研究有助于我们了解子宫内环境如何向胎儿输送过量的葡萄糖和/或脂质，并导致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，以使胎儿生长正常化。

项目成果

Postprandial Triglycerides Predict Newborn Fat More Strongly than Glucose in Women with Obesity in Early Pregnancy.

对于妊娠早期肥胖的女性来说，餐后甘油三酯比血糖更能预测新生儿的脂肪含量。

• 发表时间: 2018
• 作者: Barbour, Linda A;Farabi, Sarah S;Friedman, Jacob E;Hirsch, Nicole M;Reece, Melanie S;Van Pelt, Rachael E;Hernandez, Teri L
• 通讯作者: Hernandez, Teri L

Striking differences in estimates of infant adiposity by new and old DXA software, PEAPOD and skin-folds at 2 weeks and 1 year of life.

新旧 DXA 软件、PEAPOD 和出生后 2 周和 1 岁时的皮褶对婴儿肥胖的估计存在显着差异。

• 发表时间: 2016
• 影响因子: 3.8
• 作者: Barbour, L A;Hernandez, T L;Reynolds, R M;Reece, M S;Chartier;Anderson, M K;Kelly, T;Friedman, J E;Van Pelt, R E
• 通讯作者: Van Pelt, R E

Maternal Non-glycemic Contributors to Fetal Growth in Obesity and Gestational Diabetes: Spotlight on Lipids.

肥胖和妊娠糖尿病中母亲对胎儿生长的非血糖影响：聚焦脂质。

• 发表时间: 2018-05-09
• 影响因子: 4.2
• 作者: Barbour, Linda A;Hernandez, Teri L
• 通讯作者: Hernandez, Teri L