Napso, T. | Search bioRxiv

bioRxiv2023

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 mothers 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.

developmental biology↗

bioRxiv2020

Unbiased placental secretome characterization identifies candidates for pregnancy complications

Pregnancy requires adaptation of maternal physiology to enable normal fetal development. These adaptations are driven, in part, by the production of placental hormones. Failures in maternal adaptation and placental function lead to pregnancy complications including abnormal birthweight and gestational diabetes. However, we lack information on the full identity of hormones secreted by the placenta that mediate changes in maternal physiology. This study used an unbiased approach to characterise the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones that are important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed using mass spectrometry on cultured primary trophoblast and fluorescence-activated sorted endocrine cells from pregnant mouse dams, and a placenta secretome map containing 319 proteins was generated. Gene ontology analyses showed that a high proportion of placental secretome proteins are involved in metabolic and immune modulation, signalling and growth. The majority of proteins identified are also expressed by human placenta and several have been reported to be dysregulated in pregnancy complications. Moreover, in proof of concept studies, we found that the relative abundance of secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) was increased in women at 12 weeks of pregnancy, prior to diagnosis of gestational diabetes. Finally, we identified several transcription factors that may be important for controlling hormone production by the placenta and associate with pregnancy outcome. Thus, our observations suggest that analysis of the placental secretome could lead to the identification of new placental biomarkers of pregnancy complications.

physiology↗