There are currently over 1.9 billion adults globally who are overweight or obese. As the prevalence of obesity increases worldwide this includes women of childbearing age. Over half of all women of reproductive age in the UK are currently classed as overweight or obese. Obesity during pregnancy is known to have a negative impact on maternal health, pregnancy outcome, and the long-term cardiometabolic health of her offspring. Maternal interventions in obese pregnancy are needed to prevent transmission of poor cardiometabolic outcomes between mother and child. Maternal exercise in obese pregnancy in both humans and animal models has shown success for the prevention of adverse outcomes. As maternal obesity also results in maternal, placental, and fetal oxidative stress, antioxidant interventions to the mother may be another effective treatment. Human and mouse models of maternal obesity have shown that antioxidant supplementation can prevent an adverse offspring cardiometabolic phenotype.

Our lab has previously shown that prenatal exposure to maternal obesity results in long-term consequences for offspring cardiometabolic health in adult male offspring. However, more recent studies have highlighted that there can be sex-specific effects of the maternal environment on offspring health. In the Ozanne lab mouse model of maternal diet-induced obesity, the cardiac phenotype in female offspring is still to be established. There has also been limited exploration of the effects of maternal obesity on either male or female cardiac function in fetal life. Furthermore, there is a lack of literature on the effects of exercise and antioxidant interventions in obese pregnancy on offspring cardiac function. The aims of this thesis are therefore: (1) Chapter 3 - to characterise the sex-specific effects of maternal obesity on cardiac dysfunction in 8-week-old male and female offspring; (2) Chapter 4 - to determine the early cardiac changes in male and female fetuses exposed to maternal obesity; (3) Chapter 5 - A) to identify how the maternal environment is altered in obese pregnancy, and in particular if maternal obesity leads to hypoxic fetal conditions. B) To establish a maternal antioxidant (CoQ10) supplementation intervention during obese pregnancy; (4) Chapter 6 - to establish the effects of maternal exercise intervention during obese pregnancy on male and female fetal cardiac function.

In this thesis it was shown in Chapter 3 that young adult mouse offspring of obese mothers had sex-specific mild cardiac systolic, diastolic and electrical dysfunction in vivo, which was more severe in male offspring. This was accompanied by a mild cardiac hypertrophy phenotype, with increased cell size in both male and female offspring of obese dams. The sex-specific differences in the functional and structural phenotypes of the 8-week-old offspring heart in response to maternal obesity may help to explain the different outcomes observed in male and female risk of developing cardiovascular disease.

Chapter 4 shows that maternal obesity induced sex-specific changes in the lipidome of the fetal heart, with more changes observed in female fetuses, despite both sexes being exposed to the same maternal milieu. Changes in lipid supply to the fetal heart in obese pregnancies may drive the altered fetal cardiac transcriptome to promote a premature switch from glycolytic to β-oxidative metabolism in both sexes. The changes in lipid composition and metabolism were not accompanied by any alteration or premature maturation of fetal cardiac structure. These effects of maternal obesity on the fetal heart may contribute to the programming of altered cardiac structure and function in later life, though the precise mechanisms for this remain to be determined.

In Chapter 5, it is shown that maternal obesity resulted in fetal, but not placental, hypoxia at e13.5 in both sexes. Fetal hypoxia was associated with increased maternal fat mass and hyperinsulinaemia in obese pregnancy. Alterations in either placental size and structure or fetal growth and metabolism did not appear to underlie the development of fetal hypoxia. Obesity induced maternal iron deficiency may contribute to the development of fetal hypoxia. This chapter also established a maternal CoQ10 supplementation intervention protocol in obese pregnancy, confirming supplementation had no effects on diet palatability or maternal appetite, and did not cause any adverse maternal or fetal outcomes.

Chapter 6 showed that maternal obesity resulted in fetal growth restriction which was not rescued by maternal exercise intervention. Maternal obesity also reduced fetal insulin levels, which was sex-specifically rescued by maternal exercise in male fetuses only. Maternal obesity affected fetal in vivo cardiac function with altered heart structure and function which was not rescued by maternal exercise. These differences occurred in the absence of any changes in uterine or umbilical blood flow in response to either maternal obesity or exercise intervention.

Overall, this thesis showed the effects of maternal obesity on the adult and fetal offspring heart in both males and females. It also determined the effects of maternal exercise intervention on the fetal heart and established an antioxidant intervention protocol. Maternal interventions in obese pregnancy are important for preventing the programming of cardiometabolic disease in offspring. Further studies to fully establish the potential short- and long-term implications of interventions, in both sexes, is important for identifying effective treatment strategies in obese pregnancies to protect the health of future generations.