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

该计划的总体目标：我的NSERC-Discovery Grant计划是为了了解母亲饮食脂肪调节后代新陈代谢的机制。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器，影响新陈代谢、细胞死亡和生存途径，以及神经元或炎症过程。 背景：omega(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。适量的n-3多不饱和脂肪酸对维持妊娠也是必不可少的。我们先前已经证明，持续摄入低n-3PUFA的母猪和断奶后的日粮会对子代的血脂水平产生不利影响，同时会降低n-3PUFA的积累和脑内神经营养因子的基因表达。然而，母猪低n-3多不饱和脂肪酸的影响能否被高n-3多不饱和脂肪酸的断奶后日粮逆转尚不清楚。 我们还观察到，喂食低n-3多不饱和脂肪酸饮食的小鼠的产仔数较小。文献报道n-3多不饱和脂肪酸对妊娠结局的影响不一致。因此，重要的是确定n-3多不饱和脂肪酸的最佳用量，以维持妊娠期间的母体代谢，以获得良好的妊娠结局；并研究n-3多不饱和脂肪酸影响妊娠结局的机制。 短期内的具体目标是： 1)确定适宜妊娠结局的n-3PUFA(和/或n-6：n-3PUFA)的用量，并探讨n-3PUFA维持宫内环境的机制； 2)研究将孕期/哺乳期饲喂低n-3多不饱和脂肪酸的子代转换为高n-3多不饱和脂肪酸的断奶后日粮，是否会逆转母体日粮的影响。 实验设计：雌性C57BL/6小鼠在交配前、整个妊娠期间(目标1)和哺乳期/断奶后(目标2)饲喂不同量的n-3多不饱和脂肪酸(和/或n-6：n-3多不饱和脂肪酸)。孕妇的血浆和组织将在妊娠6.5天、12.5天和18.5天采集。植入部位将按GD 6.5进行检查；胎儿数量/体重将按GD 12.5和18.5进行记录。母体脂代谢的调节将在每个GD进行研究。母体性激素、细胞因子和胎盘FA转运蛋白的基因表达将在每个GD时被测量。在胎脑中掺入n-3多不饱和脂肪酸，并在第12.5和18.5天检测神经营养因子的基因表达。孕妇血浆和胎盘以及胎儿大脑的脂类组学图谱将识别新的脂类。在断奶时或成年后，将子代转换为高n-3PUFA的日粮对子代脂肪代谢的影响，以及脑内n-3PUFA和神经营养素基因表达的增加将被研究。 影响：这些发现将促进我们对n-3多不饱和脂肪酸在怀孕中的作用的了解。我们的发现也将有助于设计动物饲养或人类健康/怀孕的饮食。将对几名HQP进行培训。

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.