Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A(∗)STAR), 30 Medical Drive, Singapore 117609, Singapore.
Cell Metab. 2023 Jul 11;35(7):1195-1208.e6. doi: 10.1016/j.cmet.2023.06.007.
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.
哺乳动物中的母婴相互作用涉及合作与冲突。胎儿已经进化出了操纵母体生理学的方法，以增强胎盘营养物质的转移，但涉及的机制仍不清楚。印迹的 Igf2 基因在鼠类胎盘内分泌细胞中高度表达。在这里，我们表明，这些细胞中 Igf2 的缺失会损害胎盘向母体的内分泌信号传递，而不影响胎盘形态。Igf2 控制胎盘激素的产生，包括催乳素，对于建立与妊娠相关的胰岛素抵抗和将营养物质分配给胎儿至关重要。因此，缺乏胎盘内分泌 Igf2 的胎儿生长受限且低血糖。从机制上讲，Igf2 控制蛋白质合成和细胞能量稳态，这些作用依赖于胎盘内分泌细胞类型。Igf2 的缺失对后代成年后的代谢也有其他长期影响。我们的研究为在胎盘内运作的内在胎儿操纵系统提供了令人信服的证据，该系统改变了母体代谢和胎儿资源分配，对后代的代谢健康产生长期影响。
