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

项目总结/摘要 尽管有40多项针对有早产风险的孕妇的RCT干预性试验， (LGA)婴儿，目前没有明确有效的治疗，以减少胎儿过度生长超重/肥胖 (OW/OB），约占妊娠的70%。母亲肥胖仍然是LGA最常见的原因 婴儿和出生时脂肪量增加，后者是儿童代谢发展的更强预兆。 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），表明早期生活脂肪形成的影响。我们发现肥胖母亲的新生儿 和妊娠期糖尿病患者出生时肝脏脂肪比正常体重（NW）母亲多68%， 在皮下脂肪储备形成之前，母体TG越早，则预示新生儿肝脏脂肪越多。非人 灵长类动物数据支持出生时肝脏脂肪预测后来的NAFLD。我们的数据显示在可控条件下， OB母亲在整个怀孕期间的空腹和餐后甘油三酯（FTG，PPTG）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。虽然母亲PPTG独立预测了50%的新生儿脂肪早期变异（14 在妊娠后期（28周），葡萄糖增强了这种作用。这表明葡萄糖的升高 在怀孕期间刺激胎儿胰岛素（脐带C肽），当与过量的TG可用性结合时， 新生儿脂肪储存尽管一些数据支持TG在胎儿过度生长中的作用，但TG并不作为常规测量的一部分。 产科实践。部分地，这是由于便携式TG仪（类似于血糖仪）的先前不可用， 允许重复测试，我们现在已经成功地进行了试点。在这项OW/OB前瞻性队列试验中， 我们将首次获得TG和葡萄糖（通过CGM）的重复测量，以确定：1）在 什么水平的TG胎儿过度生长的风险增加，如果这发生独立或协同 葡萄糖; 2）在怀孕期间，TG暴露是最重要的，3）如果空腹与餐后TG导致 新生儿皮下脂肪较多（特定目标1;通过空气置换体积描记法）或新生儿肝脏 脂肪（特定目标2;通过磁共振波谱），独立于其他风险因素， 性别差异在我们的探索性目的中，我们将探讨胎盘脂质转运的机制， 途径可能有助于胎儿脂肪酸（FA）的传递，母体和脐带血的脂质组学特征， 与胎儿脂肪增加和脐带间充质干细胞的成脂潜能相对应。 完成这项以社区为基础的试验可能会提供令人信服的证据，以支持范式转变， 产科实践，支持测量仪TG监测，类似于妊娠期糖尿病的血糖仪，用于母亲 有胎儿过度生长的风险这些数据具有临床影响力，可以为未来的干预性试验提供信息，其中TG 用安全的TG降低剂靶向（即，高剂量欧米伽3-FA补充剂），以防止新生儿 皮下脂肪和肝脏脂肪，目的是降低儿童肥胖、NAFLD和代谢性疾病的风险。

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.