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Gestational obesity/prediabetes and folic acid supplementation program fetal one-carbon metabolism and beta cell mass Mussai, Ei-Xia


Background: Folic acid supplementation is recommended for women of childbearing age to prevent birth defects. Women with pregestational obesity (BMI≥30kg/m²) and/or diabetes are recommended to take up to 12x the recommended dose of folic acid. Concerns have been raised that elevated folic acid during pregnancy may have negative impacts on the cardiometabolic health of the mother and child. The objective of my thesis was to determine the effects of folic acid supplementation in gestational obesity/prediabetes on maternal and fetal health. Methods: Female (C57BL/6J) mice were fed from weaning a control diet (10% kcal fat; control dams) or western diet (45% kcal fat; western dams; model of obesity/prediabetes). Diets contained supplemental (10mg/kg diet) or recommended level (2mg/kg diet) folic acid. Dams (n=11-14/diet) were fed for 13 weeks prior to breeding with control males. Tissue from dams and fetal offspring were collected at embryonic day (E)18.5. Results: Prior to breeding, western dams had greater body weight and adiposity accompanied by glucose intolerance and impaired β cell function. Folic acid supplementation reduced insulin sensitivity in control dams and improved insulin sensitivity in western dams. At E18.5, western dams had larger livers and key methyl donor, S-adenosylmethionine (SAM), and it’s demethylated product, S-adenosylhomocysteine (SAH), were lower in liver, compared to control dams. Male offspring from western dams had smaller livers and higher hepatic betaine and choline compared to offspring from control dams. Female offspring from western dams had smaller livers and higher hepatic betaine compared to those from control dams. Maternal folic acid supplementation increased hepatic SAM in female offspring, but not in male offspring. Maternal diet did not affect fetal pancreas size, but male offspring from folic acid supplemented dams had greater β cell mass and β cell density compared to those from non-supplemented dams; no effect of maternal diet on β cell mass was observed in female offspring. Conclusion: Folic acid supplementation does not exacerbate adiposity and glucose tolerance in dams with gestational obesity/prediabetes. However, maternal folic acid supplementation and gestational obesity/prediabetes has sex-specific effects on hepatic one-carbon metabolism and pancreatic β cell mass in fetal offspring.

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