Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2‐mediated overgrowth

ABSTRACT The healthy development of the fetus depends on an optimal balance between fetal genetic drive for growth and the maternal ability to provide nutrients through the placenta. Nothing is known about fetal‐placental signaling in response to increased fetal demand in the situation of overgrowth. Here, we examined this question using the H19Δ13 mouse model, shown previously to result in elevated levels of Igf2. Fetal and placental weights in H19Δ13 were increased by 23% and 45%, respectively, at E19, when compared with wild‐type mice. Unexpectedly, we found that disproportionately large H19Δ13 placentas transport 20–35% less (per gram placenta) glucose and system A amino acids and have similar reductions in passive permeability, despite a significantly greater surface area for nutrient exchange and theoretical diffusion capacity compared with wild‐type mice. Expression of key transporter genes Slc2a3 and Slc38a4 was reduced by ~20%. Decreasing the overgrowth of the H19Δ13 placenta by genetically reducing levels of IgβPO resulted in up‐regulation of system A activity and maintenance of fetal overgrowth. Our results provide direct evidence that large placentas can modify their nutrient transfer capacity to regulate fetal nutrient acquisition. Our findings are indicative of fetal‐placental signaling mechanisms that limit total demand for maternal nutrients.—Angiolini, E., Coan, P. M., Sandovici, I., Iwajomo, O. H., Peck, G., Burton, G. J., Sibley, C. P., Reik, W., Fowden, A. L., Constância, M. Developmental adaptations to increased fetal nutrient demand in mouse genetic models of Igf2‐mediated overgrowth. FASEB J. 25, 1737–1745 (2011). www.fasebj.org