Fetal manipulation of maternal metabolism is a critical function of the imprinted Igf2 gene

Maternal-offspring interactions in mammals involve both cooperation and conflict. The fetus has evolved ways to manipulate maternal physiology to enhance placental nutrient transfer, but the mechanisms involved remain unclear. The imprinted Igf2 gene is highly expressed in murine placental endocrine cells. Here, we show that Igf2 deletion in these cells impairs placental endocrine signaling to the mother, without affecting placental morphology. Igf2 controls placental hormone production, including prolactins, and is crucial to establish pregnancy-related insulin resistance and to partition nutrients to the fetus. Consequently, fetuses lacking placental endocrine Igf2 are growth restricted and hypoglycemic. Mechanistically, Igf2 controls protein synthesis and cellular energy homeostasis, actions dependent on the placental endocrine cell type. Igf2 loss also has additional long-lasting effects on offspring metabolism in adulthood. Our study provides compelling evidence for an intrinsic fetal manipulation system operating in placenta that modifies maternal metabolism and fetal resource allocation, with long-term consequences for offspring metabolic health. [Display omitted] •Placenta endocrine cell (Jz) IGF2 loss impairs maternal adaptation in pregnant mice•Jz IGF2 loss reduces maternal glucose and lipid availability for fetal growth•IGF2 regulates metabolism, protein synthesis, and hormone secretion of Jz cells•Lack of Jz IGF2 programs offspring for postnatal metabolic dysfunction Lopez-Tello et al. showed in mice that a single hormone-like peptide (IGF2), encoded by an imprinted gene and expressed by placental endocrine cells, is required for the mother to adapt her glucose and lipid handling to support fetal growth. Furthermore, disruption to this process programs the offspring for metabolic dysfunction.