Mechanisms by which early-life nutritional factors program postnatal metabolism

在发育的关键时期，环境暴露可能对组织结构和新陈代谢产生永久性影响。在已知的具有这种影响的环境因素中，产妇营养是研究最充分的因素之一。最近，父亲的饮食或父亲的营养也被证明在后代的代谢规划中发挥作用。我们已经表明，母亲的饮食中蛋白质含量高，损害后代的葡萄糖代谢，而饮食中的益生元纤维含量高，减少肥胖和改善葡萄糖稳态。尽管有大量的证据表明后代代谢的程序化，但我们对早期生命事件引起组织结构和功能变化的机制的理解是不完整的。表观遗传过程已经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microRNA的表达。此外，母体营养和后代代谢之间的联系之一可能存在于母乳低聚糖中，母乳低聚糖作为婴儿肠道中的可发酵底物，从而调节肠道微生物群及其产生的代谢物。这些乳低聚糖的变化是否提供了母乳如何编程后代代谢的机制解释尚不清楚。 该项目的总体目标是确定早期产前和产后营养计划后代葡萄糖和脂质代谢的机制。总体假设是，早期暴露于高蛋白质或益生元纤维的饮食通过表观遗传机制来规划后代的代谢。母乳低聚糖，我们所示的母亲的饮食改变，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资助的发育编程大鼠模型。我们将研究表观遗传机制，主要是miRNA的表达，通过这种机制，母体饮食中蛋白质或纤维含量高的程序后代代谢。同样，我们将给雄性繁殖大鼠喂食高蛋白或高纤维的饮食，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。我们以前证明，产妇高益生元纤维饮食增加了母乳中的某些低聚糖。本研究采用人工饲养和添加低聚糖的大鼠母乳喂养方法，探讨低聚糖对幼鼠肠道菌群、肠道发育和糖脂代谢的影响机制。 这项工作的目标是扩大我们对早期营养影响（母体，父亲，出生后）影响后代长期代谢的机制的理解。将检查常见（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.