Maternal obesity increases placental transport of macronutrients, resulting in fetal overgrowth and obesity later in life. Choline participates in fatty acid metabolism, serves as a methyl donor, and influences growth signaling, which may modify placental macronutrient homeostasis and affect fetal growth. Using a mouse model of maternal obesity, we assessed the effect of maternal choline supplementation on preventing fetal overgrowth and restoring placental macronutrient homeostasis. C57BL/6J mice were fed either a high-fat (HF, 60% kcal from fat) diet or a normal (NF, 10% kcal from fat) diet with a drinking supply of either 25 mM choline chloride or control purified water, respectively, beginning 4 weeks prior to mating until gestational day 12.5. Fetal and placental weight, metabolites, and gene expression were measured. HF feeding significantly (P < 0.05) increased placental and fetal weight in the HF-control (HFCO) versus NF-control (NFCO) animals, whereas the HF choline-supplemented (HFCS) group effectively normalized placental and fetal weight to the levels of the NFCO group. Compared to HFCO, the HFCS group had lower (P < 0.05) glucose transporter 1 (GLUT1) and fatty acid transport protein 1 (FATP1) expression as well as lower accumulation of glycogen in the placenta. The HFCS group also had lower (P < 0.05) placental 4E-binding protein 1 and ribosomal protein s6 phosphorylation, which are indicators of mechanistic target of rapamycin complex 1 (mTORC1) activation favoring macronutrient anabolism. In summary, our results suggest that maternal choline supplementation prevented fetal overgrowth in obese mice at mid-gestation and improved biomarkers of placental macronutrient homeostasis.

Maternal obesity increases fetal adiposity which may adversely affect metabolic health of the offspring. Choline regulates lipid metabolism and thus may influence adiposity. This study investigates the effect of maternal choline supplementation on fetal adiposity in a mouse model of maternal obesity. C57BL/6J mice were fed either a high-fat (HF) diet or a control (NF) diet and received either 25 mM choline supplemented (CS) or control untreated (CO) drinking water for 6 weeks before timed-mating and throughout gestation. At embryonic day 17.5, HF feeding led to higher (p < 0.05) percent total body fat in fetuses from the HFCO group, while the choline supplemented HFCS group did not show significant difference versus the NFCO group. Similarly, HF feeding led to higher (p < 0.05) hepatic triglyceride accumulation in the HFCO but not the HFCS fetuses. mRNA levels of lipogenic genes such as Acc1, Fads1, and Elovl5, as well as the transcription factor Srebp1c that favors lipogenesis were downregulated (p < 0.05) by maternal choline supplementation in the HFCS group, which may serve as a mechanism to reduce fat accumulation in the fetal liver during maternal HF feeding. In summary, maternal choline supplementation improves indices of fetal adiposity in obese dams at late gestation.

Background/objectivesMaternal obesity increases the risk of gestational diabetes mellitus (GDM), which results in fetal overgrowth and long-lasting metabolic dysfunctioning in the offspring. Previous studies show that maternal choline supplementation normalizes fetal growth and adiposity of progeny from obese mice. This study examines whether supplementation of betaine, a choline derivative, has positive effects on fetal metabolic outcomes in mouse progeny exposed to maternal obesity and GDM.MethodsC57BL/6J mice were fed either a high-fat (HF) diet or a control (normal-fat, NF) diet and received either 1% betaine (BS) or control untreated (BC) drinking water 4–6 weeks before timed-mating and throughout gestation. Maternal, placental, and fetal samples were collected for metabolite and gene-expression assays.ResultsAt E12.5, BS prevented fetal and placental overgrowth and downregulated glucose and fatty acid transporters (Glut1 and Fatp1) and the growth-promoting insulin-like growth factor 2 (Igf2) and its receptor Igf1r in the placenta of HF, glucose-intolerant dams (P < 0.05). However, these effects disappeared at E17.5. At E17.5, BS reduced fetal adiposity and prevented liver triglyceride overaccumulation in HF versus NF fetuses (P < 0.05). BS fetal livers had enhanced mRNA expression of microsomal triglyceride transfer protein (Mttp) (P < 0.01), which promotes VLDL synthesis and secretion. Although we previously reported that maternal choline supplementation downregulated mRNA expression of genes involved in de novo lipogenesis in fetal livers, such alterations were not observed with BS, suggesting differential effects of betaine and choline on fetal gene expression.ConclusionWe propose a temporal-specific mechanism by which maternal BS influences fetal growth and lipid metabolic outcomes of HF mice during prenatal development.