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

母体补充胆碱对受母体肥胖和妊娠糖尿病影响的小鼠后代脂质代谢的持久影响

• 批准号: 10359140
• 负责人: Xinyin Jiang
• 金额: $ 11.78万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359140
• 关键词: Address; Affect; Animals; Betaine; Birth; Blood; Blood Glucose; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Catabolism; Child; Choline; Choline Chloride; Chronic Disease; Control Groups; DNA Methylation; Data; Deuterium; Diabetes Mellitus; Diet; Dissection; Docosahexaenoic Acids; Embryo; Epigenetic Process; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female; Fetal Macrosomia; Gene Expression; Genes; Gestational Diabetes; Goals; Health; High Fat Diet; Homeostasis; Hyperglycemia; Individual; Label; Lead; Lecithin; Life; Lipids; Lipoproteins; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; Nutrient; Nutrition Therapy; Obesity; Oral Ingestion; Organ; Outcome; Oxides; Partner in relationship; Pathway interactions; Phospholipids; Placenta; Polyunsaturated Fatty Acids; Population; Pregnancy; Pregnant Women; Production; Regulation; Research; Risk; Route; Scanning; Skeletal Muscle; Tracer; Triglycerides; Umbilical Cord Blood; Water; Weaning; Weight Gain; adverse outcome; choline supplementation; cognitive development; cost effective; design; diet-induced obesity; dietary; dietary control; drinking water; epigenetic regulation; fasting glucose; fatty acid metabolism; fatty acid transport; feeding; histone methylation; improved; insight; lipid metabolism; lipid transport; lipidomics; lipoprotein cholesterol; male; maternal obesity; methyl group; nutrition; nutritional approach; obesity risk; offspring; oxidation; postnatal; preservation; prevent; pup

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.

项目总结 在美国，超过三分之一的孕妇会受到母体肥胖的影响，并增加患肥胖症的风险 妊娠期糖尿病(GDM)，定义为妊娠期高血糖。两人都患有肥胖症 和妊娠期糖尿病导致胎儿过度生长，从而增加肥胖和心脏代谢的风险 后代晚年的疾病。尽管总体肥胖率上升，但受妊娠期糖尿病影响的婴儿 发现长链多不饱和脂肪酸(LC-PUFAs)的反常下降，如 脐带血中的二十二碳六烯酸(DHA)含量，这可能会影响DHA进入大脑 和认知发展。胆碱是一种影响不同途径的脂肪的半必需营养素 代谢，如介导脂类运输和脂类代谢基因的表观遗传控制。我们之前的研究 已经证明，母体补充胆碱(MCS)可防止胎儿过度生长并增强 肥胖和妊娠期糖尿病小鼠胚胎胎盘中LC-PUFA转运体的表达在 目前的研究，我们假设肥胖/GDM小鼠的MCS持续减少异位脂肪聚集 恢复子代小鼠不同器官的LC-PUFA状态，从而维持其代谢健康 在以后的生活中。目的1确定MCS在调节关键器官中对脂类稳态的持续影响 新陈代谢。C57BL/6J雌性小鼠将被喂养60%的高脂(HF)饲料以诱导肥胖和GDM，或者 10%正常脂肪(NF)日粮。小鼠将在水中添加25 mM的氯化胆碱或给予 在定时交配前4周控制白开水，直到断奶。我们将在两个地点解剖幼崽 断奶或断奶后6周断奶后饲喂HF(每组2只雌性和2只雄性和10只雌性)和 量化脂蛋白胆固醇、甘油三酯和脂肪酸含量以及脂代谢基因的表达 在肝脏、血液、骨骼肌和性腺脂肪垫中。目标2将确定MCS对 个体脂肪酸的代谢，特别是后代体内的LC-PUFA。脂质组学的方法将是 用于扫描所有脂肪酸种类。目标3将描述胆碱代谢的哪条途径参与 调节脂质动态平衡。我们将使用氚标记的胆碱示踪剂来追踪 体内的胆碱。我们预计，MCS在促进脂质分解代谢和输出方面具有长期的作用， 同时保持肥胖/妊娠期糖尿病母鼠后代的LC-PUFA状态，并防止他们接受HF饮食。 诱导性肥胖、脂肪肝和糖尿病。这项研究将全面确定 母体MCS对子代小鼠的脂质分布和代谢的影响 肥胖/妊娠期糖尿病。结果将为采用经济高效的营养方法来抵消持久的 母体肥胖/妊娠期糖尿病对子代脂质平衡和代谢健康的不利影响。

项目成果

Maternal Choline Supplementation and High-Fat Feeding Interact to Influence DNA Methylation in Offspring in a Time-Specific Manner.

• DOI: 10.3389/fnut.2022.841787
• 发表时间: 2022
• 期刊: Frontiers in nutrition
• 影响因子: 5
• 作者: Korsmo HW;Dave B;Trasino S;Saxena A;Liu J;Caviglia JM;Edwards K;Dembitzer M;Sheeraz S;Khaldi S;Jiang X
• 通讯作者: Jiang X

One carbon metabolism and early development: a diet-dependent destiny.

• DOI: 10.1016/j.tem.2021.05.011
• 发表时间: 2021-08
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Korsmo HW;Jiang X
• 通讯作者: Jiang X