OR20-07 Placentas from Obese Women Are Resistant to the Effect of Insulin on Triglyceride Content Ex Vivo

Background: Obesity affects 25% of pregnant women and is associated with a higher risk of neonatal complications, such as macrosomia and increased adiposity. The placenta may contribute to neonatal adiposity by accumulating and transferring excess lipid in response to maternal hyperinsulinemia. We previously found that insulin promotes a 3-fold increase in placental triglyceride (TG) content in lean women. We hypothesized that obese women have higher placental insulin resistance compared to lean women[FC1] with respect to TG content. Methods: Healthy, lean women (n=12; mean age 34±1 yrs; BMI 22±0.4 kg/m(2)) and non-diabetic, obese women (n=9; mean age 32±2 yrs; BMI 33±0.4 kg/m(2), p<0.0001) consented for placenta collection at elective c-section under fasting conditions. Placental villous explants were immediately flash frozen or cultured for 24 hours, starved, then treated for 48 hours with 0.1nM, 1nM, 10nM, or 100nM of insulin, or vehicle. Lipids were extracted from basal and treated explants using a chloroform-methanol separation protocol. TG content was quantified by spectrophotometer and normalized to weight. Data were analyzed by two-way ANOVA. Results: Basal placenta tissue from obese women contained a 1.5-fold higher level of TG compared to lean women (9.4±0.5 vs 5.7±0.5 mcg/mg, p=0.001). Placental response to insulin in lean women peaked at 1nM insulin (20.2±3.3 mcg/mg), and plateaued at higher doses of 10nM (18.6±3.3 mcg/mg) and 100nM (22.8±2.8 mcg/mg, p=NS respectively). In contrast, placenta explants from obese women required the highest insulin dose of 100 nM for maximal response (23.6±3.2 mcg/mg), and showed a gradual dose response from 0.1 nM insulin (9.5±2), 1nM (14.8±2), 10 nM (16.9±3). At 100nM insulin, the difference in TG content was variable, but on average was 2-fold higher than vehicle treated placenta (vs 11.8±2.5[FC2] [AA3] mcg/mg, p=0.002). Conclusion: Our findings indicate that placenta from obese women develop insulin resistance similar to peripheral tissues, which can be overcome by high insulin doses. This placental insulin resistance likely occurs in response to chronic hyperinsulinemia, leading to interference of insulin signaling pathways, and may protect the neonate from excessive nutrient flux.