Mechanisms by which early-life nutritional factors program postnatal metabolism

发育关键时期的环境暴露可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，母亲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新陈代谢规划中起到了作用。我们已经证明，高蛋白的母体饮食会损害子代的葡萄糖代谢，而富含益生素纤维的饮食可以减少肥胖，改善葡萄糖稳态。尽管有大量证据表明后代新陈代谢的“程序化”，但我们对早期生命事件导致晚年组织结构和功能变化的机制的理解还不完整。表观遗传过程已经成为一种可能的机制，包括DNA甲基化的改变，组蛋白尾部的修饰，以及非编码RNA的表达，如microRNAs。此外，母体营养和子代新陈代谢之间的联系之一可能存在于母体乳寡糖中，这些寡糖在婴儿肠道中充当可发酵的底物，从而调节肠道微生物区系及其产生的代谢物。这些乳寡糖的变化是否提供了一种机制上的解释，即母乳计划的后代代谢是如何未知的。*该计划的总体目标是确定早期产前和产后营养计划在后代中葡萄糖和脂肪代谢的机制。最重要的假设是，早期接触高蛋白或益生素纤维的饮食通过表观遗传机制规划后代的新陈代谢。牛奶低聚糖可能是影响后代新陈代谢反应的一个母性因素。我们的科学方法将利用我们建立的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，母亲的高蛋白或高纤维饮食规划了后代的代谢。类似地，我们将用高蛋白或高纤维的饲料喂养雄性繁殖鼠，并检查父亲饮食摄入影响后代的生化、遗传和表观遗传机制。我们以前证明了母体高益生纤维饮食增加了母体乳汁中的某些寡糖。利用人工饲养和添加牛奶低聚糖的大鼠代乳粉，我们将研究低聚糖对幼鼠肠道微生物区系、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(母体、父体、出生后)影响子代长期代谢的机制的理解。我们将考察普通食品成分(蛋白质和纤维)和新型食品成分(牛奶低聚糖)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.**