Obesity is a common health condition among women of reproductive age, and is associated with reduced fertility and increased risks of pregnancy complications such as pre-eclampsia and gestational diabetes mellitus. For this reason, women who wish to become pregnant are advised to lose weight before conception.
A revolution in weight loss treatment is currently occurring due to the licencing of a new generation of drugs that mimic the action of the gut hormone Glucacon-like peptide (GLP-1). Women are increasing choosing to use these drugs during their reproductive years to manage their weight and to treat Type II Diabetes. Although these drugs are not prescribed during pregnancy due to uncertain consequences for fetal health, their widespread use means that a growing number of women are becoming pregnant while taking GLP-1 agonists. Emerging evidence suggests that babies from these mothers have an increased risk of nutrient deficiencies and being born small for gestational age. This raises several important questions about the action of these drugs, which will be addressed in this project:
1) Emerging studies pinpoint the action of the GLP-1 receptor in the reproductive system including the ovary and brain. Does treatment with GLP-1 agonists improve fertility beyond the expected effect on weight loss?
2) Fat stores are an important source of energy and micronutrients during pregnancy and lactation, and are dynamically remodelled during the reproductive period. Does GLP-1 agonist-induced weight loss influence the provision of nutrients to the growing baby?
This project will use a combination of in-vivo models, and ex-vivo and in-vitro culture systems to understand how obesity with rapid weight loss influence ovarian function and pregnancy outcome.
Y1: Establish an in-vivo model of maternal obesity combined with GLP-1 agonist treatment. Evaluate the impact of acute weight loss on ovarian function in-vivo. Pregnancy outcome will be assessed.
Y2: Emerging findings from Y1 tested in ovarian models, and molecular mechanisms interrogated. Metabolomics performed on samples from Y1 and any changes in, e.g. lipid availability to the fetus examined.
Y3-4: Molecular hypotheses followed up using in-vivo and in-vitro models where key genes involved in the process have been manipulated.
Techniques and skills: In-vivo models of pregnancy and reproduction, ex-vivo culture of ovarian tissue, high-throughput molecular phenotyping e.g. metabolomics/transcriptomics including bioinformatics, embryo culture.
Rotation project: Examination of ovarian pathology in obese and GLP-1 agonist treated in-vivo models.