The lasting effect of maternal choline supplementation on lipid metabolism in mouse progeny affected by maternal obesity and gestational diabetes mellitus

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Project summary Maternal obesity affects more than one third of pregnant women in the U.S. and increases the risk of gestational diabetes mellitus (GDM), defined by high blood glucose during pregnancy. Both maternal obesity and GDM lead to fetal overgrowth, which subsequently increases the risk of obesity and cardio-metabolic diseases of the offspring later in life. Despite the increase in overall adiposity, GDM-affected babies demonstrate a paradoxical decrease in long-chain polyunsaturated fatty acids (LC-PUFAs) such as docosahexaenoic acid (DHA) content in the cord blood, which likely affects DHA incorporation into the brain and cognitive development. Choline is a semi-essential nutrient that affects different pathways of lipid metabolism, such as mediating lipid transport and epigenetic control of lipid metabolic genes. Our prior studies have demonstrated that maternal choline supplementation (MCS) prevented fetal overgrowth and enhanced the expression of a LC-PUFA transporter in the placenta of mouse embryos from obese and GDM dams. In the current study, we hypothesize that MCS in obese/GDM mice persistently reduces ectopic fat accumulation in different organs while restoring LC-PUFA status in mouse progeny, thereby maintaining their metabolic health later in life. Aim 1 will determine the persisting influence of MCS on lipid homeostasis in key organs regulating metabolism. C57BL/6J female mice will be fed either a 60% high-fat (HF) diet to induce obesity and GDM or a 10% normal fat (NF) diet. Mice will be either supplemented with 25mM choline chloride in water or given control plain drinking water 4 weeks prior to timed-mating until weaning of pups. We will dissect pups either at weaning or after 6 weeks of post-weaning HF feeding (n=2 females and 2 males/dam and 10 dams/group) and quantify lipoprotein-cholesterol, triglyceride, and fatty acid contents as well as lipid metabolic gene expression in the liver, blood, skeletal muscle and gonadal fat pad. Aim 2 will determine the differential effect of MCS on the metabolism of individual fatty acids, especially LC-PUFA in the offspring. A lipidomics approach will be used to scan all fatty acid species. Aim 3 will delineate which pathway of choline metabolism participates in the regulation of lipid homeostasis. We will use a deuterium labeled choline tracer to trace the metabolic fate of choline in the body. We anticipate that MCS has long-lasting effects on promoting lipid catabolism and export, while preserving LC-PUFA status in the offspring from obese/GDM dams and preventing them from HF diet- induced obesity, fatty liver, and diabetes. This study will comprehensively determine the mechanism by which MCS influences the lipid profile, distribution, and metabolism in mouse progeny affected by maternal obesity/GDM. Results will provide insights into a cost-effective nutritional approach to counteract the lasting adverse influence of maternal obesity /GDM on lipid homeostasis and metabolic health of the offspring.