Maternal Lipids and Fetal Overgrowth: Making Fat from Fat

There is increasing recognition that maternal glucose concentrations lower than those previously used for diagnosis of gestational diabetes mellitus (GDM) and targeted for treatment can result in excess fetal growth. Yet, mothers with GDM who appear to have optimal glycemic control and mothers with obesity and normal glucose tolerance still have a significantly increased risk for delivering infants who are large for gestational age, or even more importantly, who have increased adiposity at birth. What is less appreciated is that in addition to glucose, maternal lipids are also substrates for fetal fat accretion and that placental lipases can hydrolyze maternal triglycerides (TGs) to free fatty acids for fetal-placental availability. Maternal TG levels are 40% to 50% higher on average in mothers with obesity and GDM compared to those in normal-weight mothers early in pregnancy and are sustained at higher levels throughout gestation. Increasing evidence supports that maternal TG, both fasting and postprandial, are also predictors of newborn adiposity (newborn %fat), a risk factor for childhood obesity, and that early exposure is at least as strong of a risk factor as later exposure in mothers with obesity. In the setting of maternal nutrient excess and maternal insulin resistance, which lead to fetal hyperinsulinemia, excess free fatty acid exposure in the fetus may result in lipid storage and fetal fat development in subcutaneous and possibly other depots. In this commentary, we provide further evidence to make a case for targeting maternal fasting and postprandial TG in mothers with obesity who have elevated TG in early pregnancy to determine whether a TG-lowering interventional approach might limit fetal overgrowth and potentially mitigate the intrauterine contribution to childhood obesity and metabolic disease.