Maternal exercise alters rat fetoplacental stress response: Minimal effects of maternal growth restriction and high-fat feeding.

INTRODUCTION: Fetal growth restriction complicates 10% of pregnancies and increases offspring (F1) risk of metabolic disorders, including obesity and gestational diabetes mellitus (GDM). This disease predisposition can be passed onto the next generation (F2). Importantly, the risk of pregnancy complications in obese women can be exacerbated by a stressful pregnancy. Exercise can reduce adiposity and improve health outcomes in obese women and those with GDM. This study investigated the impacts of maternal growth restriction, obesity, exercise, and stress on fetal and placental endocrine function. METHODS: Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in F0 Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat (HFD) diet from weaning and, at 16 weeks, were randomly allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised only during pregnancy (PregEx). Females were mated and further randomly allocated to either undergo (Stress), or not undergo (Unstressed), physiological measurements during pregnancy. On E20, F2 fetal plasma (steroid hormones), tissues (brain, liver), and placentae (morphology, stress genes) were collected. RESULTS: Maternal growth restriction and high-fat feeding had minimal impact on fetoplacental endocrine function. PregEx and Exercise increased cross-sectional labyrinth and junctional zone areas. PregEx, but not Exercise, increased fetal deoxycorticosterone concentrations and reduced placental Hsd11b2 and Nr3c2 gene abundance. Maternal stress increased fetal corticosterone concentrations in Sedentary HFD dams and increased placental cross-sectional areas in PregEx mothers. DISCUSSION: PregEx and Stress independently dysregulates the endocrine status of the developing fetus, which may program future disease.

Exercise improves metabolic function and alters the microbiome in rats with gestational diabetes.

Gestational diabetes mellitus (GDM) is a common pregnancy complication, particularly prevalent in obese women. Importantly, exercise has beneficial impacts on maternal glucose control and may prevent GDM in "at-risk" women. We aimed to determine whether a high-fat diet (HFD) exacerbates metabolic dysfunction and alters gut microbiome in GDM and whether endurance exercise prevents these changes. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on E18 in Wistar-Kyoto rats. Female offspring were fed a Chow or HFD (23% fat) from weaning (5 weeks) and at 16 weeks randomly allocated to remain Sedentary or to an exercise protocol of either Exercise prior to and during pregnancy (Exercise); or Exercise during pregnancy only (PregEx). Females were mated (20 weeks) and underwent indirect calorimetry (embryonic day 16; E16), glucose tolerance testing (E18), followed by 24-hr feces collection at E19 (n = 8-10/group). HFD consumption in female rats with GDM exacerbated the adverse metabolic adaptations to pregnancy and altered gut microbial populations. Specifically, the Firmicutes-to-Bacteroidetes ratio was increased, due to an underlying change in abundance of the orders Clostridiales and Bacteroidales. Maternal Exercise, but not PregEx, prevented the development of metabolic dysfunction, increased pancreatic ß-cell mass, and prevented the alteration of the gut microbiome in GDM females. Our findings suggest that maternal exercise and diet influence metabolic and microbiome dysfunction in females with GDM, which may impact long-term maternal and offspring health.

Exercise initiated during pregnancy in rats born growth restricted alters placental mTOR and nutrient transporter expression.

KEY POINTS: Fetal growth is dependent on effective placental nutrient transportation, which is regulated by mammalian target of rapamycin (mTOR) complex 1 modulation of nutrient transporter expression. These transporters are dysregulated in pregnancies affected by uteroplacental insufficiency and maternal obesity. Nutrient transporters and mTOR were altered in placentae of mothers born growth restricted compared to normal birth weight dams, with maternal diet- and fetal sex-specific responses. Exercise initiated during pregnancy downregulated mTOR protein expression, despite an increase in mTOR activation in male associated placentae, and reduced nutrient transporter gene abundance, which was also dependent on maternal diet and fetal sex. Limited changes were characterized with exercise initiated before and continued throughout pregnancy in nutrient transporter and mTOR expression. Maternal exercise during pregnancy differentially regulated mTOR and nutrient transporters in a diet- and sex-specific manner, which likely aimed to improve late gestational placental growth and neonatal survival. ABSTRACT: Adequate transplacental nutrient delivery is essential for fetoplacental development. Intrauterine growth restriction and maternal obesity independently alter placental nutrient transporter expression. Although exercise is beneficial for maternal health, limited studies have characterized how the timing of exercise initiation influences placental nutrient transport. Therefore, this study investigated the impact of maternal exercise on placental mechanistic target of rapamycin (mTOR) and nutrient transporter expression in growth restricted mothers and whether these outcomes were dependent on maternal diet or fetal sex. Uteroplacental insufficiency or sham surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a chow or high-fat diet from weaning and at 16 weeks were randomly allocated to an exercise protocol: sedentary, exercised prior to and during pregnancy, or exercised during pregnancy only. Females were mated with normal males (20 weeks) and F2 placentae collected at E20. Exercise during pregnancy only, reduced mTOR protein expression in all groups and increased mTOR activation in male associated placentae. Exercise during pregnancy only, decreased the expression of amino acid transporters in a diet- and sex-specific manner. Maternal growth restriction altered mTOR and system A amino acid transporter expression in a sex- and diet-specific manner. These data highlight that maternal exercise initiated during pregnancy alters placental mTOR expression, which may directly regulate amino acid transporter expression, to a greater extent than exercise initiated prior to and continued during pregnancy, in a diet- and fetal sex-dependent manner. These findings highlight that the timing of exercise initiation is important for optimal placental function.

Maternal exercise and growth restriction in rats alters placental angiogenic factors and blood space area in a sex-specific manner.

Fetal growth and development are dependent on adequate placental nutrient transfer. The surface area of the placental villous network is a key determinant of nutrient exchange, which is regulated by vasculogenic and angiogenic factors. These factors are altered by intrauterine growth restriction (IUGR) and maternal obesity in both the first (F1) and second (F2) generations. We investigated the impact of endurance exercise in IUGR dams fed a High-fat diet on placental vasculogenesis and angiogenesis. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat diet from weaning, and at 16 weeks were further allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) and F2 placentae collected at E20. Maternal Restriction, High-fat feeding and Exercise had a minimal impact on placental regulators of vasculogenesis and angiogenesis. However, Restriction increased placental labyrinth tissue area in Chow-fed dams. PregEx induced overt adaptations, including increased VEGFA and decreased PLGF protein expression, and reduced blood space area. These alterations were sex-dependent and associated with alterations in miRNA27a, a known regulator of VEGF translation. These data highlight that maternal exercise initiated during pregnancy (PregEx) causes alterations in placental vasculogenesis and angiogenesis in a sex-dependent manner, with minimal Restriction and maternal diet effects. However, further investigation is required to determine if these adaptations are beneficial or harmful for maternal and fetoplacental outcomes.