Biomarkers of materno-fetal health: role placental endocrine mediators in normal and obese pregnancies

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Obesity during pregnancy affects maternal and infant health both during pregnancy and for long afterwards. It raises the risk of health complications like maternal diabetes during pregnancy, as well as, increases the susceptibility of the mother to develop type-2 diabetes in the years after delivery. It also leads to a range of neonatal and later life health complications in their infants, such that infants are more prone to develop metabolic diseases themselves in later life. Despite this, the mechanisms operating during pregnancy that lead to these poor pregnancy outcomes in obese women, remain unknown. The placenta is the organ that produces hormones responsible for changing the metabolism of the mother to ensure sufficient nutrients are available for fetal growth during pregnancy. However, to date, little is known about the role of placental hormone production in the development of maternal metabolic complications or in the programming of poor health outcomes of the offspring, in pregnancies where the mother is obese. Thus, this study aims to identify the importance of placental hormone production for maternal metabolism, fetal growth and offspring metabolic health, in pregnancies where the mother is obese. This will be achieved by feeding female mice from before pregnancy or only during pregnancy, a diet high in sugar and fat to cause obesity and/or metabolic dysfunction during gestation. The mother's ability to use glucose and respond to insulin, which normally regulates glucose metabolism, will then be studied during pregnancy in mice with and without a genetic defect in the placenta that disrupts placental hormone production. The metabolism of the mother will be related to growth of their pups before and after birth, as well as, to pup metabolic health in adult life. In addition, the capacity of the placenta to produce hormones with metabolic effects in the mother will be measured using the latest sequencing methods to identify the hormones responsible for the adverse pregnancy outcomes in mice that are obese and/or with metabolic dysfunction. Placental hormones identified to be important in the dysregulation of maternal metabolism in mouse pregnancies, will then be measured in the placenta and blood of lean and obese women with normal metabolism or diabetes during pregnancy to establish whether they too predict pregnancy outcome in humans. The project will provide both scientists and clinical doctors with novel information on the cause of pregnancy complications and metabolic diseases in obese women and their children. It will identify how the placenta communicates with the mother to influence fetal nutrition and growth in obese pregnancies, and ultimately, the quality of life and subsequent risk of developing life-shortening metabolic conditions in the longer term. The anticipation is that this work will identify critical hormones secreted by placenta that are responsible for the pregnancy complications and the associated programming of metabolic diseases in obese women and their families. Also, that the levels of these placental hormones in the mother may serve as early indicators of her well-being and that of her baby during pregnancy, which could be ultimately used to diagnose and develop therapies to prevent adverse pregnancy outcomes in obese women. In doing so, the proposed project has the capacity to reduce the burden of the current obesity epidemic, on the health care system.