Fetal manipulation of maternal metabolism is a critical function of Igf2 imprinting

Maternal-offspring interactions in mammals are mainly characterised by cooperation, but also conflict. Over evolutionary time, the fetus has evolved to manipulate the mother's physiology to increase nutrient transfer through the placenta, but these mechanisms are poorly characterized. The imprinted Igf2 (insulin-like growth factor 2) gene is highly expressed in mouse placental cells with endocrine functions. Here, we show that in the mouse, deletion of Igf2 in these cells leads to impaired placental endocrine signalling to the mother, but remarkably does not result in changes in placental morphology, growth or size. Mechanistically, we find that Igf2 via defective production of hormones, including prolactins, is essential for the establishment of the insulin-resistance state during pregnancy, and the appropriate partitioning of nutrients to the developing fetus. Consequently, fetuses are growth restricted and hypoglycemic, due to impaired placental glucose transfer from the mother to the fetus. Furthermore, Igf2 loss from placental endocrine cells has long-lasting effects on offspring adiposity and glucose homeostasis in adult life. Our study provides long-sought compelling experimental evidence for an intrinsic fetal manipulation system, which operates in the placenta to modify maternal metabolism and resource allocation to the fetus, with consequences for offspring metabolic health in later life.