Maternal over-nutrition and offspring health: role of translational programming of insulin action

众所周知，生活方式因素，特别是饮食和锻炼，对长期健康和寿命有很大影响。特别是，许多科学研究已经证实，肥胖会增加新陈代谢和心血管疾病以及癌症的风险。不太为人所知的是，怀孕期间母亲肥胖会永久性地影响其后代的健康，包括肥胖和发展为胰岛素抵抗的风险。这种现象被称为发展编程，在人类中主要是通过观察和关联研究来研究的，很难从这些研究中推断出潜在的机制。然而，实验动物表现出的发育编程是母体肥胖的结果，与人类的肥胖惊人地相似，因此提供了宝贵的系统来研究也适用于人类的机制。我们一直在研究怀孕期间喂食高脂肪/高糖饮食的雌性小鼠的后代。我们发现有证据表明，这些后代对荷尔蒙胰岛素的代谢反应受损，这种反应会持续到成年，并已知会增加日后代谢和心血管疾病的风险。与这些对整个动物的胰岛素敏感性的影响相关联的是，在脂肪组织(它在协调其他组织的新陈代谢中起着核心作用)中，我们检测到了介导对胰岛素反应的特定蛋白质水平的变化。这些蛋白质中的一种，IRS-1，已经被认为是胰岛素对脂肪和肌肉细胞作用的关键控制点。通过比较高脂肪/高糖饮食或正常饮食母亲后代的脂肪细胞，我们发现有证据表明，肥胖母亲的后代中IRS-1蛋白水平较低，因为该蛋白质的合成减少。我们认为这反映了一类小RNA分子的作用，即microRNAs或miRs，它们抑制含有合成IRS-1蛋白所需信息的信使RNA分子的翻译。事实上，在喂食高脂肪/高糖饮食的母亲的后代细胞中，我们已经显示出一种以IRS-1为靶标的microRNAs(miR-126)的水平发生了变化。这是一项令人兴奋的突破，为进一步的研究指明了道路，这些研究将为在分子水平上发生什么导致不利的发育编程，以及可以采取什么措施来防止它提供新的线索。我们现在想做四件事。首先，我们想要识别由于母亲过度营养而在脂肪细胞中表达水平的其他microRNAs。全基因组RNA测序和阵列技术的进步使这成为一项相对简单的工作。结果将告诉我们这种变化的范围，并利用数据库中可获得的关于潜在目标的信息，说明总体影响可能是什么。其次，我们将进行实验，以确定包括miR-126在内的程序化microRNAs的靶标。我们以前曾在其他情况下做过类似的实验，因此我们有信心获得明确的数据。第三，我们将研究包括miR-126在内的miRNAs在调节IRS-1水平、胰岛素敏感性和脂肪细胞代谢功能中的作用。我们可以通过操纵(上调或下调)单个microRNA的水平来实现。最后，我们将调查简单的生活方式干预，如怀孕期间增加运动量，是否可以在脂肪细胞中的microRNAs和蛋白质水平上缓解发育编程，以及这是否与整个有机体水平上的代谢反应改善有关。我们相信，这些研究将极大地促进对孕期母亲过度营养引起的发育规划的原因和后果的理解，以及如何改善这种规划。重要的是，我们在动物模型上的实验将为关于如何管理相应的人类状况的辩论提供信息。

It is well known that lifestyle factors, particularly diet and exercise, have a big effect on long-term health and lifespan. In particular, many scientific studies have established that obesity increases risk of metabolic and cardiovascular diseases and cancer. It is less well known that maternal obesity during pregnancy can permanently influence the health of her offspring including their risk of being obese and developing insulin resistance. This phenomenon, known as developmental programming, has been studied in humans largely by observational and association studies, from which it is difficult to deduce underlying mechanisms. However, laboratory animals show developmental programming as a consequence of maternal obesity that is strikingly similar to that seen in humans, and therefore provide valuable systems in which to investigate mechanisms that will also be applicable in humans. We have been studying the offspring of female mice that have been fed a high-fat/high-sugar diet during pregnancy. We have found evidence that these offspring have impaired metabolic responses to the hormone insulin that persist into adulthood and that are known to increase the risk of metabolic and cardiovascular diseases in later life. Associated with these effects on insulin sensitivity of the whole animal, in fat tissue (which has a central role in orchestrating metabolism of other tissues) we detected changes in the levels of specific proteins that mediate responses to insulin. One of these proteins, IRS-1, was already known to be a key control point for insulin action on fat and muscle cells. By comparing fat cells taken from the offspring of mothers fed high-fat/high-sugar or normal diets, we found evidence that levels of IRS-1 protein are lower in the offspring of obese mothers because the synthesis of the protein is decreased. We believe this reflects the action of a class of small RNA molecules, microRNAs or miRs for short, that inhibit the translation of messenger RNA molecules containing the information required for synthesis of IRS-1 protein. In fact in cells from offspring of mothers fed the high-fat/high-sugar diet we have shown changes in the level of one of the microRNAs (miR-126) that is known to target IRS-1. This is an exciting breakthrough that points the way for further studies that will shed new light on what is happening at a molecular level to cause adverse developmental programming, and what might be done to prevent it.There are four things we would now like to do. First, we want to identify other microRNAs whose levels are programmed in fat cells by maternal over-nutrition. Advances in genome wide RNA sequencing and array technology make this a relatively straightforward exercise. The results will inform us about the scope of such changes and, using information on potential targets that is available in databases, what the overall effects might be. Second we will carry out experiments to identify targets of programmed microRNAs including miR-126. We have done similar experiments before in other contexts so we are confident of getting clear-cut data. Third, we will investigate the role of miRNAs including miR-126 in programming IRS-1 levels, insulin sensitivity and metabolic function in fat cells. We can by manipulating (up or down) the levels of individual microRNAs. Finally we will investigate whether simple lifestyle interventions, such as increased amounts of exercise during pregnancy, can alleviate developmental programming at the level of microRNAs and proteins in fat cells, and whether this correlates with improved metabolic responses at the whole organism level. We believe these studies will significantly advance understanding of the causes and consequences of developmental programming arising from maternal over-nutrition during pregnancy, and how such programming might be ameliorated. Importantly our experiments in animal models will inform the debate on how to manage the corresponding human condition.