Abstract

The placenta mediates maternal-fetal exchange and has historically been regarded as a passive conduit for nutrients. However, emerging evidence suggests that the placenta actively responds to nutritional and metabolic signals from the mother and the fetus. We propose that the placenta integrates a multitude of maternal and fetal nutritional cues with information from intrinsic nutrient-sensing signaling pathways to match fetal demand with maternal supply by regulating maternal physiology, placental growth, and nutrient transport. This process, which we have called placental nutrient sensing, ensures optimal allocation of resources between the mother and the fetus to maximize the chances for propagation of parental genes without jeopardizing maternal health. We suggest that these mechanisms have evolved because of the evolutionary pressures of maternal undernutrition, which result in decreased placental growth and down-regulation of nutrient transporters, thereby limiting fetal growth to ensure maternal survival. These regulatory loops may also function in response to maternal overnutrition, leading to increased placental growth and nutrient transport in cases of maternal obesity or gestational diabetes. Thus, placental nutrient sensing modulates maternal-fetal resource allocation to increase the likelihood of reproductive success. This model implies that the placenta plays a critical role in mediating fetal programming and determining lifelong health.