Understanding how maternal nutrition impacts offspring metabolism: The role of dietary fats

了解母体营养如何影响后代新陈代谢：膳食脂肪的作用

• 批准号: RGPIN-2020-04130
• 负责人: Cheema, Sukhinder
• 金额: $ 2.4万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739678
• 关键词: Understanding; how; maternal; nutrition; impacts

OVERALL AIM OF THE PROGRAM: My NSERC-Discovery Grant program is to understand the mechanisms by which maternal dietary fats regulate offspring metabolism. The long-term goal is to better understand how fatty acids (FA) act as regulators of gene expression to affect metabolism, cell death and survival pathways, and neuronal or inflammatory processes. BACKGROUND: The omega (n)-3 polyunsaturated fatty acids (PUFA) are transported across the placenta for proper growth and development of the fetus. An optimal amount of n-3 PUFA is also essential for maintaining pregnancy. We have previously demonstrated that sustained exposure to maternal and post-weaning diets low in n-3 PUFA have adverse effects on offspring lipid levels, along with lower accretion of n-3 PUFA and a lower gene expression of neurotrophins in brain. However, whether the effects of maternal diets low in n-3 PUFA can be reversed by post-weaning diets high in n-3 PUFA is not known. We also observed a smaller litter size in mice fed a low n-3 PUFA diet. Literature reports inconsistent effects of n-3 PUFA on pregnancy outcome. It is thus important to establish the optimum amount of n-3 PUFA, to maintain maternal metabolism during pregnancy, for a favorable pregnancy outcome; and to investigate the mechanisms by which n-3 PUFA influences pregnancy outcome. The specific objectives in the short-term are: 1) To establish the amount of n-3 PUFA (and/or n-6:n-3 PUFA) for favorable pregnancy outcome, and to investigate the mechanisms by which n-3 PUFA maintain the in utero environment; 2) To investigate whether switching the offspring fed a low n-3 PUFA diet during gestation/lactation, to a post-weaning diet high in n-3 PUFA, will reverse the effects of maternal diets. EXPERIMENTAL DESIGN: Female C57BL/6 mice will be fed diets varying in the amount of n-3 PUFA (and/or n-6:n-3 PUFA) before mating, throughout gestation (Objective 1), and lactation/post-weaning (Objective 2). Maternal plasma and tissues will be collected at gestation day (GD) 6.5, 12.5 and 18.5. Implantation sites will be checked at GD 6.5; fetal numbers/weight will be recorded at GD 12.5 and 18.5. The regulation of maternal lipid metabolism will be studied at each GD. Maternal sex-steroids, cytokines, and gene expression of placental FA transporters will be measured at each GD. Incorporation of n-3 PUFA in fetal brain, and the gene expression of neurotrophins will be measured at GD 12.5 and 18.5. Lipidomics profile of maternal plasma and placenta, and of fetal brain, will identify novel lipids. The effects of switching the offspring to a diet high in n-3 PUFA, at weaning, or in adulthood, will be studied on offspring lipid metabolism, and the accretion of n-3 PUFA and neurotrophins gene expression in brain. IMPACT: The findings will advance our knowledge on the role of n-3 PUFA in pregnancy. Our findings will also help to design diets for animal breeding, or towards human health/pregnancy. Several HQP will be trained.

本组织的总体目标：我的NSERC发现资助计划是为了了解母体膳食脂肪调节后代代谢的机制。长期目标是更好地了解脂肪酸（FA）如何作为基因表达的调节因子影响代谢，细胞死亡和存活途径以及神经元或炎症过程。背景：ω（n）-3多不饱和脂肪酸（PUFA）通过胎盘转运，以促进胎儿的正常生长和发育。最佳量的n-3 PUFA对于维持妊娠也是必不可少的。我们以前已经证明，持续暴露于母体和断奶后的饮食低n-3 PUFA对后代的脂质水平有不利影响，沿着较低的n-3 PUFA的增加和较低的基因表达的神经营养因子在大脑中。然而，n-3 PUFA含量低的母体饮食的影响是否可以通过n-3 PUFA含量高的断奶后饮食来逆转尚不清楚。我们还观察到喂食低n-3 PUFA饮食的小鼠的窝仔数较小。文献报告n-3 PUFA对妊娠结局的影响不一致。因此，重要的是要建立最佳量的n-3 PUFA，以维持母体代谢在怀孕期间，一个良好的妊娠结局;并调查的机制，n-3 PUFA影响妊娠结局。 短期内的具体目标是：1）确定有利妊娠结局的n-3 PUFA（和/或n-6：n-3 PUFA）的量，并研究n-3 PUFA维持子宫内环境的机制; 2）研究将妊娠/哺乳期间饲喂低n-3 PUFA饮食的后代转换为断奶后高n-3 PUFA饮食是否会逆转母体饮食的影响。 实验设计：在交配前、整个妊娠期（目标1）和哺乳期/断奶后（目标2），雌性C57 BL/6小鼠将饲喂n-3 PUFA（和/或n-6：n-3 PUFA）含量不同的饲料。将在妊娠第6.5、12.5和18.5天（GD）采集母体血浆和组织。将在GD 6.5检查着床部位;将在GD 12.5和18.5记录胎仔数量/体重。将在每次GD时研究母体脂质代谢的调节。将在每次GD时测量母体性类固醇、细胞因子和胎盘FA转运蛋白的基因表达。将在GD 12.5和18.5测量胎仔脑中n-3 PUFA的掺入和神经营养因子的基因表达。母体血浆和胎盘以及胎儿脑的脂质组学谱将鉴定新的脂质。将研究在断奶时或成年时将后代切换到n-3 PUFA高的饮食对后代脂质代谢以及脑中n-3 PUFA和神经营养因子基因表达的增加的影响。影响：这些发现将促进我们对n-3 PUFA在妊娠中作用的认识。我们的研究结果也将有助于为动物繁殖或人类健康/怀孕设计饮食。将培训几名HQP。