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

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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.