SUN-530 - Placenta-Secreted Fatty Acid Binding Protein 4 Programs Offspring Glucose Homeostasis

Maternal obesity is a prominent health issue during pregnancy that puts mother and fetus at risk for complications such as gestational diabetes or altered fetal growth, respectively. Preclinical and human studies report adverse metabolic health outcomes, including increased susceptibility of obesity and type 2 diabetes, in offspring of obese pregnancies. The placenta, an endocrine organ formed during pregnancy to support fetal growth, responds to maternal nutrient status and fetal demand. We have shown that perturbing placental nutrient sensor pathways is sufficient to induce metabolic dysfunction in the offspring. Complementary to placental nutrient sensing and transport is the endocrine capacity of the placenta, which coordinates secretion of hormones and other proteins throughout gestation. The placental secretome is an emerging area of research with high importance due to the potential for placenta-secreted proteins to reach fetal tissues. In our diet-induced maternal obesity model characterized by increased maternal body weight before and during pregnancy, and elevated blood glucose, serum insulin, and islet insulin content during pregnancy, we found increased placental expression and secretion of fatty acid binding protein 4 (FABP4). FABP4 has previously been shown to be elevated in obesity states and alter metabolic tissue function and glucose homeostasis. We hypothesized that increased levels of placenta-secreted FABP4 during maternal obesity perturbs offspring β-cell development and long-term islet function, and reducing placental FABP4 is sufficient to protect offspring glucose homeostasis. To assess the baseline impact of placental FABP4 on offspring metabolic health trajectory, we employed a murine model of placenta-specific FABP4 deletion (FABP4KOpl) during a normal weight pregnancy. Neonatal and adult body weights were not significantly impacted in FABP4KOpl offspring. However, adult FABP4KOpl males displayed significantly elevated blood glucose levels and impaired glucose tolerance without differences in insulin sensitivity. These results suggest that FABP4KOpl males have pancreatic β-cell mass or functional deficits, which are being explored. Taken together, we are the first to report that placenta-secreted FABP4 may positively contribute to glucose control in a normal weight pregnancy. Further studies of FABP4KOpl in the context of maternal obesity, where FABP4 is elevated, will be vital to understanding mechanisms underlying determinants of long-term metabolic health. Our findings will provide a more accurate landscape of how the maternal environment, placenta-secreted proteins, and offspring metabolic tissues interact to regulate fetal programming and long-term health trajectory.

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