Metabolic and cardiorenal adaptations to pregnancy in females born small on a high fat diet and benefits of endurance exercise training

Abstract

Uteroplacental insufficiency is the major cause of intrauterine growth restriction in Western society and is often associated with adult metabolic, cardiovascular and renal diseases. Recent studies have reported that these phenotypes are exacerbated with “second hits” such as pregnancy and obesity in women born small. Pregnancy is the greatest physiological challenge facing women and, indeed, females born small are at increased risk of gestational diabetes and hypertension. Interestingly, there has been a significant increase in the number of reproductive age women who are either overweight or obese over the past few decades. Being obese or overweight is suggested to exacerbate the pregnancy complications in women born small. Importantly, exercise is reported to prevent or delay the metabolic and cardiovascular dysfunction in individuals born small. Thus, the development of targeted interventions in growth-restricted females may prevent them from developing metabolic and cardiorenal dysfunctions during pregnancy.

Uteroplacental insufficiency, resulting in growth restriction, was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 (E18) in Wistar-Kyoto rats. Female offspring consumed a Chow or a high fat diet (HFD; 43% kcal from fat) from 5 weeks and were mated at 20 weeks with normal male. Systolic blood pressure was measured by tail cuff in all rats prior to pregnancy (week 18). Female rats remained Sedentary or exercised on treadmills for 4 weeks before pregnancy and throughout pregnancy or only during the last two thirds of pregnancy. Rats were individually placed in an indirect open-circuit calorimeter chamber (CLAMS; 24 hours) at E16 to measure their energy expenditure and spontaneous physical activity. Systolic blood pressure was measured by tail cuff and non-fasted glucose tolerance test was performed at E18. At E19, rats were individually placed in a metabolic cage to collect urine and blood was taken by tail vein to calculate estimated glomerular filtration rate (eGFR) via measurement of urinary and plasma creatinine. Maternal plasma, pancreas, and heart were collected at E20. Fetuses and placentae were weighed and sex was confirmed using qPCR (SRY).

In Chapter 3, the effect high fat feeding on the metabolic adaptations during pregnancy in rats born small was explored as was whether exercise before and during pregnancy is more beneficial in preventing these complications than exercise during pregnancy alone. Control and Restricted rats consuming a HFD were significantly heavier with more dorsal fat (+40%) and higher plasma leptin concentrations (+80%) compared to Chow-fed rats, irrespective of exercise interventions (P<0.05). Compared to Sedentary, both exercise interventions increased oxygen consumption (VO2) and respiratory exchange ratio (RER) in Restricted Chow-fed rats only (P<0.05). HFD induced glucose intolerance in Control females and exacerbated glucose intolerance in Restricted females that remained Sedentary throughout the study (P<0.05). The development and exacerbation of glucose intolerance in Control and Restricted females were prevented by exercise initiated prior to and continued during pregnancy. Furthermore, exercise before and during pregnancy increased insulin secretion in Chow-fed females and increased β-cell mass in HFD Control and Restricted females (P<0.05). No differences in spontaneous physical activity were detected across the groups. Of interest, metabolic dysfunction in Control and Restricted females was not improved by exercise initiated during pregnancy.

In Chapter 4, we determined if high fat feeding exacerbates the known adverse cardiorenal adaptations to pregnancy in rats born small and whether exercise before and during pregnancy is more beneficial in preventing these complications than exercise during pregnancy alone. Sedentary Control females on a HFD altered renal function (increased eGFR; P<0.05) and this was not affected by exercise. Compared to Control, Restricted females that remained Sedentary also had an increased eGFR (P<0.05), which was not influenced by HFD or restored by both exercise interventions. No changes in pre-pregnancy systolic blood pressure were identified in all experimental groups. When pregnant, Restricted Chow- fed rats and both Control and Restricted females on a HFD had an impaired cardiovascular adaptation, with a greater reduction in systolic blood pressure during late gestation (P<0.05), and only exercise initiated before and continued during pregnancy prevented this. Additionally, Control and Restricted rats that exercised prior to and during pregnancy had an increased heart weight (normalized to tibial length) irrespective of diet at E20, indicative of physiological cardiac hypertrophy.

Finally, Chapter 5 of the thesis investigated the effect of high fat feeding and endurance exercise training on the fetal outcomes in rats born small. Maternal growth restriction and HFD did not affect male and female fetal and placental weights in mothers that remained Sedentary throughout the study. Exercise initiated before and continued during pregnancy increased fetal weight in both male and female fetuses of mothers on a Chow diet, but not in mothers on a HFD. No difference in male and female fetal and placental weights were observed when mothers exercised during pregnancy only.

In summary, HFD revealed and exacerbated glucose intolerance in pregnant females born of normal birth weight and born small, respectively. These were prevented by the lifestyle intervention of exercise, potentially due to improved β-cell mass. The improved glucose intolerance in Chow-fed Restricted that initiated exercise prior to pregnancy was likely contributed by increase in glucose-stimulated insulin secretion. This study also suggests that females born small have altered cardiorenal adaptations to pregnancy. Although impaired metabolic and cardiovascular adaptations during pregnancy were prevented by exercise prior to and during pregnancy, renal function was not affected by both exercise interventions. This study highlights that modifiable risk factors, such as diet and exercise, can have beneficial effects in the mother during pregnancy; particularly for females born small. By identifying females who are at high risk, especially in women born small and overweight/obese women, will ensure preventative intervention strategies to minimise adverse outcomes during pregnancy and in later life. Ultimately, these approaches may reduce the perpetuating cycle of metabolic and cardiorenal disease risk to future generations.