Lipid Metabolism in Pregnancy: Adipose-Placental Interactions

Viviparity, or the development of live young within the body of the parent, is a fundamental biological process that is used by mammals to protect their offspring during the vunerable period of early life. In order to support viviparity mammals have evolved a host of mechanisms to allow the efficient transfer of nutrition from mother to offspring. A crucial adaptation was the evolution of the placenta. The placenta is a transient organ with multiple functions that ultimately support pregnancy. In the placenta the maternal and fetal blood come into close proximity, allowing the exchange of nutrients and waste products. In addition, the placenta produces hormones that signal to the mother's body and direct the nutrients that she obtains from food toward the fetus.
Pregnancy in mammals is thought to comprise of two phases; early pregnancy when the mother increases her appetite in order to store energy in her fat depots, and late pregnancy when she releases this energy and nutrients toward the rapidly growing fetus. Some nutrients are in particularly high demand by the developing fetus. One class of these nutrients are the essential fatty acids (EFAs). EFAs come into the body in the diet, they are particularly abundant in marine life, and they cannot be synthesised by mammals. These fatty acids are necessary for the development and growth of the brain and eye. Lack of these nutrients in the maternal diet causes blindness and neurodevelopmental disorders in humans. Because they are so important, EFAs are preferentially transported to the developing fetus during pregnancy. However, we currently do not understand how the mother achieves this, nor how EFAs cross the placental barrier to enter the fetal circulation so they can be used to build the brain and eye.
In this project we hope to explain how EFAs travel from the maternal diet to the fetus. We suspect that EFAs are stored in maternal fat stores even prior to pregnancy, and that in the second half of pregnancy they are selectively released and travel to the liver where they are packaged into a form that can be recognised by placental cells. At the placental barrier we think that the EFAs are recognised by a specific transporter molecule that can move them inside the cells. The final part of the project will investigate how the placenta communicates with the mother so that she releases fats from her fat stores. We believe that specific placental hormones signal directly to the maternal fat to allow the energy and nutrients there to be liberated at the best time to support fetal growth.
It is important to understand how fatty acids, including EFAs, are transferred from mother to fetus for several reasons. Firstly, this is a fundamental biological process that underlies all mammalian reproduction, from human pregnancy to livestock farming. Secondly, many women are poorly nourished and this becomes more important during pregnancy when the mother may have insufficient nutrient stores to support the healthy development of the baby. Many intervention strategies have tried to increase the amount of EFAs given to malnourished mothers in pregnancy to try to improve the health of the baby. However, these trials have met with mixed success. In order to fully support healthy pregnancy, early life and lifelong health, we need to understand much more about the processes by which the placenta and mother communicate to ensure adequate nutrient flow.

There are fundamental gaps in our knowledge about how maternal adipose tissue responds to the reproductive period, including which specific lipid species are synthesised and accumulated during the different stages of pregnancy and how they are selectively released to enable fetal growth and maternal energy maintenance. The essential fatty acids (EFAs) and their derivatives, the long and very long chain polyunsaturated fatty acids (LC-PUFAs) are preferentially transported by the mother to the fetus, a process known as biomagnification, and failure to supply them is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting complex interactions between dietary EFA intake and the molecular mechanisms of maternal supply. Maternal adipose tissue storage and release of EFA may represent a critical control point for the process of biomagnification.
The placenta regulates the flow of resources from mother to offspring during pregnancy. This is achieved by multiple mechanisms including the production of hormones that enter the maternal circulation and modulate her metabolism. The regulation of maternal lipid metabolism by placental hormones is broadly described but our understanding of how specific fatty acid species including LC-PUFAs are selectively mobilised and transported from mother to fetus, and how placental signalling elicits this response is still sketchy.
In this project we will combine unbiased lipidomics, genetic models of placental transport modulation, multiomics analysis of adipose tissue and deep phenotyping of murine pregnancy models to understand the fundamental mechanisms by which maternal adipose tissue and the placenta cooperate to provide fatty acids to the developing fetus.