Mechanisms by which early-life nutritional factors program postnatal metabolism

发育关键时期的环境暴露会对组织结构和代谢产生永久性影响。在已知有这种影响的环境因素中，母亲的营养是研究得最充分的因素之一。最近，父亲的饮食或父亲的营养也被证明在后代的代谢程序中起作用。我们已经证明，高蛋白质的母亲饮食会损害后代的葡萄糖代谢，而高益生元纤维的饮食会减少肥胖并改善葡萄糖稳态。尽管有大量证据表明后代的新陈代谢是程序化的，但我们对早期生活事件导致生命后期组织结构和功能变化的机制的理解是不完整的。表观遗传过程已成为一种合理的机制，包括DNA甲基化的改变，组蛋白尾部的修饰和非编码rna（如microRNAs）的表达。此外，母体营养与后代代谢之间的联系之一可能存在于母乳低聚糖中，低聚糖在婴儿肠道中充当可发酵底物，从而调节肠道微生物群及其产生的代谢物。这些牛奶低聚糖的变化是否提供了母乳如何控制后代代谢的机制解释尚不清楚。***本计划的总体目标是确定早期产前和产后营养计划对后代葡萄糖和脂质代谢的机制。最重要的假设是，早期接触富含蛋白质或益生元纤维的饮食可以通过表观遗传机制调节后代的代谢。牛奶低聚糖，我们表明改变与母亲的饮食，可能是一个母亲的因素，影响后代的代谢反应。***我们的科学方法将利用我们完善的nserc资助的发展规划老鼠模型。我们将研究表观遗传机制，主要是miRNA表达，通过母体高蛋白质或高纤维饮食计划后代代谢。同样，我们将给雄性繁殖大鼠喂食高蛋白质或高纤维的食物，并研究父亲的饮食摄入量影响后代的生化、遗传和表观遗传机制。我们之前证明，母体高益生元纤维饮食增加了母乳中的某些低聚糖。通过人工饲养和添加低聚糖的大鼠代乳剂，研究低聚糖对幼龄大鼠肠道菌群、肠道发育和糖脂代谢的影响机制。这项工作的目的是扩大我们对早期营养影响（母系、父系、产后）影响后代长期代谢的机制的理解。将研究常见（蛋白质和纤维）和新型（牛奶低聚糖）食品成分的影响

Environmental exposures during critical periods of development can have permanent effects on tissue structure and metabolism. Of the environmental factors known to have such effects, maternal nutrition is one of the most well-studied. More recently, fathers' diet or paternal nutrition has been shown to also play a role in metabolic programming of offspring. We have shown that maternal diets high in protein impair glucose metabolism in offspring while diets high in prebiotic fiber reduce adiposity and improve glucose homeostasis. Despite an abundance of evidence for the programming' of offspring metabolism, our understanding of the mechanisms by which early life events cause changes in tissue structure and function later in life is incomplete. Epigenetic processes have emerged as a plausible mechanism and include alterations in DNA methylation, modification of histone tails and expression of non-coding RNAs such as microRNAs. Furthermore, one of the links between maternal nutrition and offspring metabolism may be found in maternal milk oligosaccharides, which act as fermentable substrate in the infant gut and thereby modulate gut microbiota and the metabolites they produce. Whether or not changes in these milk oligosaccharides provides a mechanistic explanation of how maternal milk programs offspring metabolism is not known.***The overall objective of this program is to identify mechanisms by which early prenatal and postnatal nutrition program glucose and lipid metabolism in offspring. The overarching hypothesis is that early exposure to diets high in protein or prebiotic fiber program offspring metabolism via epigenetic mechanisms. Milk oligosaccharides, shown by us to be altered with maternal diet, may be one maternal factor that influences metabolic response in offspring.***Our scientific approach will capitalize on our well-established NSERC-funded rat model of developmental programming. We will examine the epigenetic mechanisms, chiefly miRNA expression, by which maternal diets high in protein or fiber program offspring metabolism. Similarly, we will feed male breeder rats diets high in protein or fiber and examine the biochemical, genetic and epigenetic mechanisms by which fathers' dietary intake affects the offspring. We previously demonstrated that a maternal high prebiotic fiber diet increased certain oligosaccharides in maternal milk. Using artificial rearing and rat milk replacer supplemented with milk oligosaccharides, we will examine the mechanisms by which oligosaccharides affect gut microbiota, intestinal development and glucose and lipid metabolism in young rats.***The goal of this work is to expand our understanding of the mechanisms by which early nutritional influences (maternal, paternal, postnatal) affect long-term metabolism in offspring. The effects of common (protein and fiber) and novel (milk oligosaccharides) food ingredients will be examined.**