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

众所周知，生活方式因素，特别是饮食和运动，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，肥胖会增加代谢、心血管疾病和癌症的风险。孕妇在怀孕期间的肥胖会永久性地影响其后代的健康，包括他们肥胖和产生胰岛素抵抗的风险，这一点鲜为人知。这种现象被称为发育规划，主要通过观察和关联研究在人类中进行研究，从中很难推断出潜在的机制。然而，实验动物由于母体肥胖而表现出与人类惊人相似的发育程序，因此为研究同样适用于人类的机制提供了有价值的系统。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。我们已经发现证据表明，这些后代对胰岛素激素的代谢反应受损，这种反应会持续到成年，并且已知会增加晚年患代谢和心血管疾病的风险。与这些对整个动物胰岛素敏感性的影响相关联的是，在脂肪组织（在协调其他组织的代谢中起核心作用）中，我们检测到介导胰岛素反应的特定蛋白质水平的变化。其中一种蛋白质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/高糖饮食和正常饮食的母亲的后代的脂肪细胞，我们发现证据表明，肥胖母亲的后代的IRS-1蛋白水平较低，因为蛋白质的合成减少了。我们认为这反映了一类小RNA分子（简称microRNAs或miRs）的作用，它们抑制含有IRS-1蛋白合成所需信息的信使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，我们已经发现了一种已知靶向IRS-1的microrna （miR-126）水平的变化。这是一个令人兴奋的突破，为进一步的研究指明了道路，这些研究将揭示在分子水平上发生了什么，导致了不良的发育程序，以及如何预防它。现在我们想做四件事。首先，我们想要确定其他的microrna，其水平是由母体过度营养在脂肪细胞中编程的。全基因组RNA测序和阵列技术的进步使得这项工作相对简单。结果将告诉我们这些变化的范围，并利用数据库中可用的关于潜在目标的信息，了解可能产生的总体影响。其次，我们将开展实验来鉴定包括miR-126在内的程序化microrna的靶标。我们以前在其他情况下做过类似的实验，所以我们有信心得到明确的数据。第三，我们将研究包括miR-126在内的mirna在编程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（上升或下降）单个microrna的水平。最后，我们将研究简单的生活方式干预，如怀孕期间增加运动量，是否可以减轻脂肪细胞中microrna和蛋白质水平上的发育编程，以及这是否与整个生物体水平上的代谢反应改善相关。我们相信这些研究将极大地促进对怀孕期间母亲营养过剩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.