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The effect of metformin intervention on the programming of cardiometabolic health in offspring of obese pregnancy



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Schoonejans, Josca Mariette 


Obesity and/or diabetes during pregnancy is associated with obesity, metabolic and cardiovascular disease in the offspring. Clinically relevant interventions are required to break the transgenerational cycle of obesity. Metformin is used to treat GDM in the UK and RCTs are investigating metformin as a candidate for implementation in pregnancies complicated by obesity or polycystic ovary syndrome. However, metformin crosses the placenta and long-term offspring follow-up is sparse in both humans and animal models. Data throughout the life-course, investigation of potentially sexually dimorphic effects and cardiovascular outcomes are especially lacking. Using a mouse model, this thesis aimed to determine the short- and long-term effects on adiposity and metabolic health in male and female offspring in early life (neonatal growth trajectory, Chapter 3), young adulthood (8 weeks, Chapter 4) and older age (12 months, Chapter 5). It also aimed to investigate cardiovascular phenotypes in adult offspring at different points across the life-course (3, 6 and 12 months of age, Chapter 6). Exposure to an obesogenic diet from pre-conception and during pregnancy and lactation increased maternal bodyweight, fat mass and food intake. Maternal obesity introduced hypertrophic adiposity in both male and female offspring at 8 weeks of age and this increased adiposity was maintained until 6 months. After 6 months, sex differences emerged: male offspring of obese dams were heavier and showed hypertrophic and hyperplastic adiposity with adipose tissue inflammation and insulin resistance, whereas adiposity in female offspring became less prominent with age. Maternal metformin treatment decreased maternal fat mass and this difference was maintained until late pregnancy. The metformin intervention also increased gestation length and did not prevent the intrauterine growth restriction and catchup growth seen in offspring of obese pregnancy. In offspring, the metformin intervention did not correct the adiposity phenotype programmed by maternal obesity, but instead led to exaggerated adiposity and adipose tissue dysfunction in a sex- and a time-dependent manner. In both sexes, exposure to metformin during obese pregnancy caused adipocyte hypertrophy at 8 weeks of age prior to development of obesity. In males this was associated with adipocyte hyperplasia, inflammation and local insulin resistance. Although male offspring of control-fed and obese dams underwent age-related adipocyte hyperplasia, adipocyte number failed to increase in ageing metformin-exposed male offspring. Combined with more extensive macrophage infiltration and increased liver weight this leads to the hypothesis that adipose tissue expansion capacity is restricted in metformin-exposed males, resulting in adipose tissue dysfunction and ectopic lipid deposition. In female metformin-exposed offspring, adiposity in young adulthood was associated with alternate macrophage activation and an improvement in whole-body insulin sensitivity. However, after 6 months of age female metformin-exposed offspring diverged from other groups in viii body weight and fat mass, showing inflammatory adiposity at 12 months of age associated with both peripheral and systemic insulin resistance as well as hyperinsulinaemia. Maternal obesity also affected cardiovascular health of male and female offspring. In males, offspring of obese dams had diastolic dysfunction leading to pressure overload and hyperdynamic systolic function in absence of changes in blood pressure. In contrast, female offspring of obese dams had increased blood pressure throughout life associated with diastolic dysfunction at 3 months. The metformin intervention corrected some of the changes that were observed with maternal obesity. In male offspring, prenatal metformin halted progression of diastolic dysfunction with age but also introduced other independent cardiovascular changes. In female offspring, prenatal metformin corrected the hypertension seen in young offspring of obese dams, but by 12 months of age female metformin-exposed offspring had developed obesity-induced hypertension. In conclusion, this thesis reports sex- and age-specific effects of maternal obesity and prenatal metformin intervention, illustrating the need for short- and long-term follow-up of both male and female offspring exposed to prenatal interventions.





Ozanne, Susan


obesity, fetal programming, gestational diabetes, metformin, adipose tissue, metabolic health, cardiovascular disease, pregnancy, mouse models


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
British Heart Foundation 4-year PhD Studentship (FS/16/53/32729) British Society for Neuroendocrinology COVID-19 Exceptional Support Grant 2020 - For Final Year PhD Students