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多个RCT介入试验，孕妇有可能交付较大的胎龄 （LGA）婴儿，目前尚无明显有效的治疗方法来减少超重/肥胖症的胎儿过度生长 （OW/OB），占怀孕的约70％。母亲肥胖仍然是LGA的最常见原因 婴儿和出生时脂肪质量增加，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了，40％已经表现出非酒精性脂肪肝病 （NAFLD），暗示着早期的脂肪生成影响。我们已经证明了肥胖母亲的新生儿 妊娠糖尿病的肝脏脂肪比正常体重（NW）母亲的肝脏脂肪高68％，并且 在皮下脂肪储存之前，较早的母体TG预测了新生儿肝脂肪。非人类 灵长类动物的数据支持，肝脏脂肪在出生时预测后来NAFLD。我们的数据表明，在受控条件下， 在整个怀孕期间，OB母亲的禁食和餐后甘油三酸酯（FTG，PPTG）的生命高30-40％。 此外，FTG和PPTG比葡萄糖，BMI或脂肪质量，胰岛素抵抗，更可预测新生脂肪， 或体重增加。尽管产妇PPTG独立预测了早期新生脂肪的50％（14 WKS），到后来的怀孕（28周），这种作用被葡萄糖增强。这表明葡萄糖稍后增加 在怀孕中，刺激胎儿胰岛素（脐带C肽），当与过量的TG相结合时， 新生儿脂肪存储。尽管某些数据支持TG在胎儿过度生长中，但TG并未作为例行的一部分测量 产科实践。在某种程度上，这是由于先前无法使用便携式TG仪表（类似于血糖仪） 允许重复测试，我们现在已经成功驾驶。在OW/OB的这项前瞻性队列试验中 怀孕，我们将首次获得TG和葡萄糖的重复度量（通过CGM），以定义：1） 胎儿过度生长的风险的水平增加，如果发生在独立于或与之协同作用的情况下 葡萄糖; 2）当怀孕时，TG暴露是最重要的，3）如果禁食与餐后TG导致 较大的新生儿皮下脂肪（特定目的1；通过空气置换术）或新生儿肝脏 脂肪（特定目标2；通过磁共振光谱），与其他风险因素无关 性别差异。在我们的探索目的中，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）的递送，母体和脐带血的脂质组信号 与增加的胎儿脂肪积聚相对应，以及脐带间充质干细胞的成脂潜力。 这项基于社区的审判的完成可能会提供令人信服的证据，以支持范式转变 母亲的产科练习，类似于妊娠糖尿病的糖糖仪，类似于仪表 有胎儿过度生长的风险。这些数据在临床上有影响力，可能会为将来的介入试验提供介绍，其中TG 以安全的降低TG剂（即高剂量的欧米茄3-FA补充剂）的靶向针对新生儿 皮下和肝脏脂肪，目的是降低肥胖，NAFLD和代谢疾病的儿童时期风险。