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: 10402851
• 负责人: LINDA Anne BARBOUR
• 金额: $ 66.11万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402851
• 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 in pregnancy; 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.

项目摘要/摘要 尽管有40多项随机对照试验对有胎龄过大风险的孕妇进行干预试验 (LGA)婴儿，目前还没有明显有效的治疗方法来减少超重/肥胖的胎儿过度生长 (OW/OB)，约占怀孕的70%。母亲肥胖仍然是LGA的最常见原因 婴儿出生时脂肪质量增加，后者是儿童新陈代谢发育的更强先兆 疾病。五分之一的学龄前儿童已经肥胖，40%的儿童已经表现出非酒精性脂肪肝 (NAFLD)，表明早期生活中存在成脂影响。我们已经证明，肥胖母亲所生的新生儿 与正常体重(NW)母亲相比，妊娠期糖尿病母亲出生时肝脏脂肪多68%，并且 较早的母体TG，在皮下脂肪储备形成之前，预测新生儿肝脏脂肪。非人 灵长类动物的数据支持出生时的肝脏脂肪预测以后的NAFLD。我们的数据显示，在受控条件下， OB母亲在整个怀孕期间的空腹和餐后甘油三酯(FTG，PPTG)水平要高出30%-40%。 此外，FTG和PPTG比血糖、BMI或脂肪量、胰岛素抵抗、 或者体重增加。尽管母亲PPTG独立预测了新生儿肥胖早期(14%)的50%的变异 在怀孕后期(28周)，这种影响被葡萄糖放大。这表明晚些时候血糖升高 在怀孕期间刺激胎儿胰岛素(脐带C肽)，当与过剩的甘油三酯可利用性结合时，增加 新生儿脂肪储存库。尽管一些数据支持TG在胎儿过度生长中的作用，但TG不是常规测量的一部分 产科实践。在一定程度上，这是由于以前没有便携式TG计(类似于血糖仪)，该仪器 允许重复测试，我们现在已经成功地进行了试验。在这项OW/OB前瞻性队列试验中 我们将首次获得重复测量的甘油三酯和血糖(由CGM)来定义：1) 什么水平的甘油三酯会增加胎儿过度生长的风险，如果这种情况独立发生或与之协同发生 2)怀孕期间的TG暴露是最重要的，3)如果空腹和餐后的TG结果是 更多的新生儿皮下脂肪(特定目标1；通过空气置换体积描记)或在新生儿肝脏中 脂肪(特定目标2；通过磁共振波谱)，独立于其他风险因素，并考虑到 性别差异。在我们的探索目标中，我们将询问胎盘脂质运输的机制 途径可能促进胎儿脂肪酸(FA)的分娩，母体和脐带血的脂肪组学特征 与胎儿脂肪堆积增加以及脐带间充质干细胞的成脂潜能相对应。 这项基于社区的试验的完成可能会提供令人信服的证据，支持在 支持孕妇甘油三酯监测的产科实践，类似于妊娠期糖尿病的血糖仪 有胎儿过度生长的风险。在临床上，这些数据可能会为未来的介入试验提供信息，在这项试验中，TG 以安全的降甘油三酯药物(即高剂量的omega 3-FA补充剂)为目标，以防止新生儿过多 皮下脂肪和肝脏脂肪，旨在降低儿童患肥胖症、非酒精性脂肪肝和代谢性疾病的风险。