High fructose intake during pregnancy adversely affects insulin resistance, lipid profiles, and affects placental gene expression of nutrient transporters and angiogenesis in rat dams and their pregnant offspring

Fructose intake has increased over the past several decades due to high consumption of sugary foods and drinks. In non-pregnant humans and animals, high fructose intake results in hyperlipidemia, insulin resistance and weight gain, although its effects on metabolic adaptations to pregnancy and on offspring have not been well-defined thus far. Three studies were conducted for this thesis with the overall purpose of assessing the effects of fructose intake on physiological changes related to pregnancy in dams and their pregnant offspring. In each study, female rats received a 10% fructose solution (FR) or distilled water (CONT) prior to and during pregnancy. Offspring remained on the same diet treatment as their mothers (Dams) prior to and during pregnancy. Glycemic control was assessed by measuring glucose and insulin concentrations throughout the study and an oral glucose tolerance test toward the end of pregnancy. Body weights and body composition were also measured. Gene expression for nutrient transporters and vascular development were measured in the placenta of Dams and Offspring. The first study compared the effects of fructose intake between pregnant and age-matched, non-pregnant rats (Dam-FR, n=6; NP-FR, n=5; Dam-CONT, n=4; NP-CONT, n=6). Dams and NP rats given fructose solution had increased concentrations of insulin (P=0.0031) and triglyceride (P=0.0476) compared with CONT (Dams and NP). Pregnancy did not accentuate the effects of FR on these outcomes. The second study compared the metabolic effects of intake of the fructose solution vs. distilled water on pregnant rats (Dams) and their female offspring (Offspring) when pregnant (Dam-FR, n=16; Dam-CONT, n=14) and female offspring when pregnant (Offspring-FR, n=10; Offspring-CONT, n=10). Fructose intake increased body weight (P=0.0003), plasma glucose, insulin and triglyceride concentrations (all P<0.0001) and % fat mass (P<0.0001) in Dams and Offspring. Offspring-FR had higher plasma triglyceride concentrations than Dams-FR (P=0.0099) and both CONT groups. Placenta from Dams-FR and Offspring-FR had increased mRNA expression of FABP1 (P=0.0004) but not other nutrient transporters (GLUT1 and SNAT2). Markers of angiogenesis (VEGF-A, P=0.0015; VEGFR-2, P=0.0014) were altered and CD31 expression was reduced (marker of endothelial cells; P=0.0129) with FR. Placentae and fetuses from Dams and Offspring given FR weighed less than those from CONT groups (P=0.0002 and P=0.0004, respectively). The third study compared the effect of intake of fructose (Dam-FR, n=14) vs. distilled water (Dam-CONT, n=12) on body weight and metabolic characteristics in two sequential pregnancies. Body weights were higher in the second than the first pregnancy (P<0.0001). Plasma glucose concentrations were higher in the second pregnancy at the mid-way point (P=0.0341) compared with the first pregnancy. Insulin concentrations were higher throughout the second vs. the first pregnancy (P=0.0182). Fructose intake did not exacerbate these effects. Overall, intake of a 10% fructose solution induces insulin resistance and hypertriglyceridemia in pregnant rats and the adverse effects of fructose intake during pregnancy were similar in the first and second pregnancy. Hypertriglyceridemia was more pronounced in pregnant Offspring consuming FR. This suggests that the effect of dietary programming on lipid metabolism occur in conjunction with a physiological challenge and points to the potential of dietary intake of fructose to adversely influence insulin resistance and lipid metabolism in mothers and their offspring when pregnant. Alterations in maternal metabolites and body composition were correlated with changes in placental development, particularly nutrient transporters, angiogenesis and vascular development. Overall changes in maternal metabolic profiles and placental development may be related to adverse health outcomes (such as hyperlipidemia) in the mother and offspring in later life

High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring

Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant’s gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10–13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4–7) and late pregnancy (gestational day 19–21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development

Lifetime Exposure to a Constant Environment Amplifies the Impact of a Fructose-Rich Diet on Glucose Homeostasis during Pregnancy

The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy. Markers of maternal hepatic metabolism were differentially influenced, as the gene expression of acetyl-CoA-carboxylase was raised in Gen1 given fructose and controls, whereas glucose transporter 5 and fatty acid synthase expression were only raised with fructose. Gen1 rats weighed more than Gen0 throughout the study, although fructose feeding raised the percent body fat but not body weight. We show that long-term habituation to the living environment has a profound impact on the animal’s metabolic responses to nutritional intervention and pregnancy. This has important implications for interpreting many studies investigating the influence of maternal consumption of fructose on pregnancy outcomes and offspring to date

Table_1_High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring.DOCX

Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant’s gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10–13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4–7) and late pregnancy (gestational day 19–21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development.</p

Table_2_High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring.DOCX

<p>Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant’s gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10–13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4–7) and late pregnancy (gestational day 19–21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development.</p