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

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.

In the UK and around the globe, the prevalence of obesity during pregnancy is increasing relentlessly. This is worrying as obesity adversely affects maternal and infant health both during and after pregnancy. It increases the risk of pregnancy complications such as gestational diabetes (GDM) and leads to neonatal and later health conditions including type-2 diabetes in the offspring. In obese women, the metabolic responses to pregnancy are often exaggerated. Maternal metabolic alterations are signalled, in part, by changes in placental hormone production. However, to date, little is known about the role of placental endocrine function in determining pregnancy outcomes in obese mothers. Thus, this study aims to identify the role of placental hormone production for maternal metabolism, fetal growth and offspring metabolic health, in pregnancies where the mother is obese. It will use the latest sequencing techniques to identify the hormones secreted from the placenta that are dysregulated in mouse pregnancies associated with maternal obesity. It will then use a new model of genetically-induced placental endocrine malfunction in mice (achieved by cell-specific deletion of the imprinted growth gene, Igf2, which controls placental endocrine cell formation and function), to test the hypothesis that abnormal placental hormone production contributes to the metabolic maladjustments of the obese mother and the developmental programming of the offspring. Placental hormones important in the deregulation of maternal metabolism in mouse pregnancies will then be measured in the placenta and blood of lean and obese women with normal metabolism or GDM to establish whether they too predict pregnancy outcome in humans. The ultimate goal of this work is identify placental biomarkers that indicate materno-fetal health during gestation and can be used to diagnose, or as therapy targets to prevent, pregnancy complications and the associated programming impacts in obese women.

Enhancing quality of life and health: In the UK, >33% of women are overweight or obese at their first antenatal appointment. This is particularly worrying, as obesity during pregnancy increases the risk of gestational diabetes and type-2 diabetes in the mother, and to a range of neonatal and later health complications in their infants. Therefore, by understanding the mechanisms operating during pregnancy that lead to poor pregnancy outcomes in obese women and their children, this project could improve the nation's health and wealth in both the short and long term. In particular, our studies will identify placental biomarkers that indicate materno-fetal health during gestation and that can be explored as diagnostic tools or therapeutic targets to prevent pregnancy complications and the long-term impacts associated with maternal obesity and thereby, reduce the burden of the current obesity epidemic on the health care system.

The economy: NHS funds are used to monitor and to treat women and their babies where the pregnancy is complicated by maternal obesity and/or placental malfunction. Moreover, the NHS spends further funds treating people with type 2 diabetes, heart disease and obesity, which are linked to adverse pregnancy conditions. By discovering the factors secreted by the placenta which control maternal metabolic health and fetal development in obese pregnancies, the outcomes of this project have the potential to reduce the immediate and life-long costs of maternal obesity, on the health care system; thereby benefiting the British economy.

Commercialisation: This project has the potential to identify novel factors produced by the placenta that are responsible for the maladjustment of maternal metabolism during pregnancy. These factors will likely serve as early indicators of maternal wellbeing and fetal growth and health in both obese and leaner women, which could be exploited commercially as diagnostic tools and therapy targets for pregnancy complications like gestational diabetes. The expression of such factors in the placenta at birth may also indicate pregnancy wellbeing and predict infant's future risk of diseases, allowing timely treatment strategies.

Contributing to policy making and legislation: By understanding how obesogenic diets and placental endocrine function interact to influence maternal and offspring metabolic health, this work may be important when devising policies on the advice given to overweight and obese women and in managing and treating pregnancy complications.

Contributing to public understanding of science, economy and society issues: By communicating the findings through publications, media coverage and at outreach events, this work will raise public knowledge of obesogenic diets, obesity and placental endocrine function in the control of prenatal growth, development of pregnancy complications and the origins of metabolic diseases.

Worldwide scientific advancement: Little is known about the identity and importance of placental endocrine mediators to pregnancy outcome and long-term health in women who are overweight or obese. The proposed work addresses this fundamentally and clinically important knowledge gap which is of benefit to academic and clinical scientists in a wide range of disciplines (obesity, metabolism, developmental programming, pregnancy/reproductive biology, endocrinology, epigenetics).

Delivering and training highly skilled researchers: This work will build track record and reputation of the laboratory and provide training for all researchers involved in the proposed research (genome editing, placenta biology, in vivo studies of whole body physiology, the latest RNA and protein sequencing techniques and the translation of mouse findings to studies of human pregnancy). These activities thus, increase the number of highly skilled scientists in the UK.