Triglycerides as a Predictor of Newborn Subcutaneous and Liver Fat: Contributors to Fetal Fat Accretion in Obese Pregnancies

甘油三酯作为新生儿皮下脂肪和肝脏脂肪的预测因子：导致肥胖妊娠中胎儿脂肪堆积的因素

• 批准号: 10209574
• 负责人: LINDA Anne BARBOUR
• 金额: $ 66.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-07 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10209574
• 关键词: Accounting; Address; Adipocytes; Air; Attenuated; Birth; Birth Weight; Blood; Body mass index; C-Peptide; Childhood; Clinical; Communities; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Discipline of obstetrics; Dose; Dual-Energy X-Ray Absorptiometry; Exhibits; Fasting; Fatty Acids; Fatty acid glycerol esters; Fetal Macrosomia; Fetus; Future; Gene Proteins; Gestational Age; Gestational Diabetes; Glucose; Goals; Hyperinsulinism; Infant; Insulin; Insulin Resistance; Intervention Trial; Lead; Life; Lipase; Lipids; Liver; Magnetic Resonance Spectroscopy; Measures; Mesenchymal Stem Cells; Metabolic Diseases; Metabolism; Monitor; Mothers; Newborn Infant; Obesity; Omega-3 Fatty Acids; Oranges; Outcome; Overweight; Pancreas; Pathway interactions; Placenta; Plethysmography; Predictive Value; Pregnancy; Pregnant Women; Production; Prospective cohort; RNA; Resistance profile; Retrospective Studies; Risk; Risk Factors; Role; Sampling; Sex Differences; TG gene; Testing; Time; Triglycerides; Umbilical Cord Blood; Umbilical cord structure; Weight; Weight Gain; Woman; Work; base; boys; effective intervention; effective therapy; fatty acid transport; fetal; girls; glucose monitor; in utero; indexing; intergenerational; intrahepatic; lipid biosynthesis; lipid transport; lipidomics; maternal obesity; meter; newborn adiposity; non-alcoholic fatty liver disease; nonhuman primate; novel strategies; obese mothers; obesity in children; obesity risk; portability; prevent; response; sex; stem cells; subcutaneous; synergism; targeted treatment

Project Summary/Abstract Despite more than 40 RCT interventional trials in pregnant women at risk for delivering large-for-gestational age (LGA) infants, there is currently no clearly effective treatment to reduce fetal overgrowth in overweight/obesity (OW/OB), which account for ~70% of pregnancies. Maternal obesity remains the most common cause of LGA infants and increased fat mass at birth, the latter a stronger harbinger for the development of childhood metabolic disease. One in five preschoolers is already obese, and 40% already exhibit non-alcoholic fatty liver disease (NAFLD), suggesting early life adipogenic influences. We have shown that newborns from mothers with obesity and gestational diabetes are born with 68% more liver fat than those from normal-weight (NW) mothers, and earlier maternal TG, before subcutaneous fat stores have developed, predicted newborn liver fat. Non-human primate data support that liver fat at birth predicts later NAFLD. Our data show that under controlled conditions, OB mothers have 30-40% higher fasting and postprandial triglycerides (FTG, PPTG) throughout pregnancy. Moreover, FTG and PPTG are more predictive of newborn fat than glucose, BMI or fat mass, insulin resistance, or weight gain. Although maternal PPTG independently predicted 50% of the variance in newborn fat early (14 wks), by later pregnancy (28 wks) this effect was augmented by glucose. This suggests that rising glucose later in pregnancy stimulates fetal insulin (cord C-peptide), and when combined with excess TG availability, augments newborn fat storage. Although some data support TG in fetal overgrowth, TG are not measured as part of routine obstetric practice. In part, this is due to prior unavailability of a portable TG meter (similar to a glucometer) that allows repeated testing, which we have now successfully piloted. In this prospective cohort trial in OW/OB pregnancies we will, for the first time, obtain repeated measures of TG and glucose (by CGM) to define: 1) at what level of TG the risk of fetal overgrowth increases, and if this occurs independent of or in synergy with glucose; 2) when in pregnancy the TG exposure is most important, 3) if fasting vs postprandial TG results in greater newborn subcutaneous fat (Specific Aim 1; by air-displacement plethysmography) or in newborn liver fat (Specific Aim 2; by magnetic resonance spectroscopy), independent of other risk factors and accounting for sex differences. In our Exploratory Aim, we will interrogate mechanisms by which placental lipid transport pathways may facilitate fetal fatty acid (FA) delivery, the lipidomic signatures of maternal and cord blood which correspond with increased fetal fat accretion, and the adipogenic potential of umbilical mesenchymal stem cells. Completion of this community-based trial may provide compelling evidence to support a paradigm shift in obstetric practice that endorses meter TG monitoring, similar to glucometers in gestational diabetes, for mothers at risk for fetal overgrowth. Clinically impactful, these data may inform a future interventional trial in which TG are targeted with safe TG-lowering agents (i.e., high dose omega 3-FA supplements) to prevent excess newborn subcutaneous and liver fat, with the goal of decreasing childhood risk for obesity, NAFLD, and metabolic disease.

项目概要/摘要 尽管有超过 40 项针对存在大于胎龄风险的孕妇的随机对照试验干预试验 （LGA）婴儿，目前尚无明确有效的治疗方法来减少超重/肥胖胎儿过度生长 (OW/OB)，约占妊娠的 70%。产妇肥胖仍然是 LGA 的最常见原因 婴儿和出生时脂肪量增加，后者是儿童代谢发育的更强预兆 疾病。五分之一的学龄前儿童已经肥胖，40% 的人已经患有非酒精性脂肪肝 （NAFLD），表明生命早期的脂肪形成影响。我们已经证明，肥胖母亲所生的新生儿 妊娠期糖尿病患者出生时的肝脏脂肪比正常体重 (NW) 母亲的肝脏脂肪多 68%，并且 在皮下脂肪储存形成之前，较早的母体TG可预测新生儿肝脏脂肪。非人类 灵长类动物的数据支持出生时的肝脏脂肪可以预测以后的 NAFLD。我们的数据表明，在受控条件下， 产科母亲在整个怀孕期间的空腹和餐后甘油三酯（FTG、PPTG）要高出 30-40%。 此外，FTG 和 PPTG 比葡萄糖、BMI 或脂肪量、胰岛素抵抗、 或体重增加。尽管母亲 PPTG 独立预测了早期新生儿脂肪差异的 50%（14 周），到妊娠后期（28 周），葡萄糖增强了这种效应。这表明稍后血糖升高 怀孕期间会刺激胎儿胰岛素（脐带 C 肽），当与过量的 TG 可用性相结合时，会增强 新生儿脂肪储存。尽管一些数据支持 TG 与胎儿过度生长有关，但 TG 测量并未作为常规的一部分 产科实践。部分原因是之前没有便携式 TG 计（类似于血糖仪）， 允许重复测试，我们现在已经成功进行了试点。在 OW/OB 的前瞻性队列试验中 怀孕期间，我们将首次重复测量 TG 和葡萄糖（通过 CGM）来定义：1) 什么水平的 TG 会增加胎儿过度生长的风险，以及这种情况是否独立发生或协同发生 葡萄糖; 2) 怀孕期间 TG 暴露最为重要，3) 空腹与餐后 TG 是否会导致 更大的新生儿皮下脂肪（具体目标 1；通过空气置换体积描记法）或新生儿肝脏 脂肪（具体目标 2；通过磁共振波谱），独立于其他风险因素并考虑 性别差异。在我们的探索性目标中，我们将探讨胎盘脂质转运的机制 途径可能促进胎儿脂肪酸（FA）的输送，这是母体和脐带血的脂质组学特征， 与胎儿脂肪堆积增加以及脐带间充质干细胞的脂肪形成潜力相对应。 这项基于社区的试验的完成可能会提供令人信服的证据来支持范式转变 产科实践支持对母亲进行血糖仪 TG 监测，类似于妊娠糖尿病中的血糖仪 存在胎儿过度生长的风险。这些数据具有临床影响力，可能会为未来的干预试验提供信息，其中 TG 以安全的 TG 降低剂（即高剂量 omega 3-FA 补充剂）为目标，以防止新生儿过量 皮下脂肪和肝脏脂肪，目标是降低儿童肥胖、NAFLD 和代谢疾病的风险。