Supervisor: Amanda Sferruzzi-Perri
Project 1: Role of placental endocrine function in the outcomes of obese pregnancies
Within the UK and around the globe, the prevalence of obesity during pregnancy is increasing. This is worrying as obesity during pregnancy adversely affects maternal and infant health both during pregnancy and for long afterwards. Maternal obesity is associated with pregnancy complications like gestational diabetes and abnormal birthweight and predisposes the infant to develop metabolic diseases in later life. In obese women, metabolic responses to pregnancy, such as the acquisition of insulin resistance and glucose intolerance are intensified. Changes in placental hormone production during pregnancy are thought to play a key role in regulating maternal metabolic alterations. Despite this, little is known about the role of placental endocrine function in promoting changes in maternal metabolism and insulin resistance in obese pregnancies and its importance for the health of the offspring in later life. The current PhD project will address this knowledge gap by:
- Determining the identify of hormones secreted from the placenta that are dysregulated in mouse pregnancies associated with maternal obesity.
- Examining the role of placental hormone production in driving maternal metabolic maladaptations and offspring programming in obese mouse pregnancies in vivo.
To achieve these aims, we will perform proteomic profiling of placental endocrine cells isolated from mouse dams with diet-induced obesity. Candidates will be verified in placental and maternal blood samples and related to the metabolic state of the dam in control and obese pregnancies. A new and robust model of genetically-induced placental endocrine malfunction in mice (achieved by selectively manipulating the placental endocrine cells using conditional deletion of the imprinted growth gene, Igf2, which controls their formation and function), will then be used to test the hypothesis that abnormal placental hormone production contributes to the metabolic maladjustments of the mother during gestation and the developmental programming of the offspring, in pregnancies associated with obesity.
Relevant references:
1. Musial B, Fernandez-Twinn DS, Duque-Guimaraes D, Carr SK, Fowden AL, Ozanne SE, and Sferruzzi-Perri AN. Exercise alters obese mothers' tissue insulin sensitivity and lipid handling in mice. Physiol Reports. 2019;7(16): e14202.
2. Musial B, Vaughan OR, Fernandez-Twinn DS, Voshol P, Ozanne SE, Fowden AL and Sferruzzi-Perri AN. A Western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice. J Physiol. 2017;595(14):4875-92.
3. Sferruzzi-Perri AN, Vaughan OR, Haro M, Cooper WN, Musial B, Charalambous M, Pestana D, Ayyar S, Ferguson-Smith AC, Burton GJ, Constancia M and Fowden AL. An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB. 2013;27(10):3928-37.
Project 2: Role of placental endocrine malfunction in the programming of disease in offspring
During pregnancy, nutrients must be supplied to the fetus for growth but also to the mother to maintain the pregnancy. This nutrient balance depends on the placenta, an organ that develops during pregnancy to transfer nutrients to the fetus and that secretes hormones into the mother with metabolic effects. Impaired placental function disrupts the materno-fetal nutrient balance and results in major pregnancy complications, including abnormal birthweight with both immediate and long-lasting effects on offspring health. However, our understanding of the importance of placental endocrine function in the control of fetal growth and long-term health of the offspring is unknown. To address this knowledge gap, we have developed new and robust models of genetically-induced placental endocrine malfunction in mice (achieved by selectively altering the placental endocrine cells using conditional genetic manipulation of the imprinted growth gene, Igf2, which controls their formation and function). Using this approach, we have found that placental endocrine malfunction is associated with programmed changes in insulin and glucose handling of both the female and male offspring in adult life. This PhD will extend these important findings by:
- Identifying which tissues in the offspring are affected by placental endocrine malfunction and responsible for the altered glucose and insulin handling of offspring in later life.
- Exploring the intrauterine mechanisms by which metabolic organs of the developing offspring are programmed by placental endocrine malfunction.
This will be achieved by studying the function of key metabolic organs in female and male offspring that were supported by placentas with endocrine malfunction. Particularly, it will assess tissue insulin production and action in the offspring into adult life by using in vivo physiological, molecular, histological and biochemical assays. It will also employ molecular methods to explore epigenetic changes in key metabolic organs of the offspring during development.
Relevant references:
1. Musial B, Fernandez-Twinn DS, Duque-Guimaraes D, Carr SK, Fowden AL, Ozanne SE, and Sferruzzi-Perri AN. Exercise alters obese mothers' tissue insulin sensitivity and lipid handling in mice. Physiol Reports. 2019;7(16): e14202.
2. Musial B, Vaughan OR, Fernandez-Twinn DS, Voshol P, Ozanne SE, Fowden AL and Sferruzzi-Perri AN. A Western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice. J Physiol. 2017;595(14):4875-92.
3. Sferruzzi-Perri AN and Camm EJ. The programming power of the placenta. Front Physiol 2016;7:33.