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: 9903390
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903390
• 关键词: Address; Affect; Animals; Betaine; Birth; Blood; Blood Glucose; Brain; Cardiovascular Diseases; Catabolism; Child; Choline; Choline Chloride; Chronic Disease; Control Groups; DNA Methylation; Data; Deuterium; Diabetes Mellitus; Diet; Disease; 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; cardiometabolism; choline supplementation; cognitive development; cost effective; design; drinking water; epigenetic regulation; fasting glucose; fatty acid metabolism; fatty acid transport; feeding; histone methylation; improved; insight; lipid metabolism; lipid transport; 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.

项目概要 母亲肥胖影响了美国三分之一以上的孕妇，并增加了患病的风险 妊娠糖尿病（GDM），定义为妊娠期间高血糖。产妇肥胖 和 GDM 会导致胎儿过度生长，从而增加肥胖和心脏代谢的风险 后代在以后的生活中患上疾病。尽管总体肥胖率有所增加，但受 GDM 影响的婴儿 证明了长链多不饱和脂肪酸（LC-PUFA）的反常减少，例如 脐带血中的二十二碳六烯酸 (DHA) 含量，可能会影响 DHA 融入大脑 和认知发展。胆碱是一种半必需营养素，影响脂质的不同途径 代谢，例如介导脂质转运和脂质代谢基因的表观遗传控制。我们之前的研究 已证明母体胆碱补充剂（MCS）可防止胎儿过度生长并增强 肥胖和 GDM 小鼠胚胎胎盘中 LC-PUFA 转运蛋白的表达。在 目前的研究中，我们假设肥胖/GDM 小鼠中的 MCS 持续减少异位脂肪积累 不同的器官，同时恢复小鼠后代的 LC-PUFA 状态，从而维持其代谢健康 在以后的生活中。目标 1 将确定 MCS 对调节关键器官脂质稳态的持续影响 代谢。 C57BL/6J 雌性小鼠将被喂食 60% 高脂肪 (HF) 饮食以诱导肥胖和 GDM，或者 10% 正常脂肪 (NF) 饮食。给小鼠补充 25mM 氯化胆碱水溶液或给予 定时交配前 4 周控制白水，直至幼犬断奶。我们将在以下时间解剖幼崽 断奶或断奶后 HF 喂养 6 周后（n=2 只雌性和 2 只雄性/母鼠和 10 只母鼠/组）和 量化脂蛋白胆固醇、甘油三酯和脂肪酸含量以及脂质代谢基因表达 存在于肝脏、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，尤其是后代中的 LC-PUFA。脂质组学方法将是 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 脂质稳态的调节。我们将使用氘标记的胆碱示踪剂来追踪 体内的胆碱。我们预计 MCS 对促进脂质分解代谢和输出具有长期持久的作用， 同时保持肥胖/GDM母鼠后代的LC-PUFA状态并防止它们接受HF饮食- 诱发肥胖、脂肪肝、糖尿病。本研究将全面确定其机制 MCS 影响受母体影响的小鼠后代的脂质谱、分布和代谢 肥胖/GDM。结果将提供对具有成本效益的营养方法的见解，以抵消持久的影响 母亲肥胖/GDM 对后代脂质稳态和代谢健康的不利影响。