Does PABP4 control diet-induced obesity, by acting as a master regulator of metabolism-related gene expression?

肥胖是世界范围内的一个主要问题，三分之一的成年人超重，八分之一的人肥胖，相当于全球6亿人。肥胖的日益流行给英国带来了巨大且迅速增长的健康和经济负担(2015年英国62.9%的成年人超重或肥胖，自1993年以来增加了14.9%)，因为肥胖与严重的健康问题有关，如2型糖尿病、心脏病和中风。此外，越来越多的证据表明，孕妇肥胖会影响婴儿的终生健康，增加她们肥胖和患心血管疾病的风险。肥胖的增加在很大程度上是由越来越多的人采用所谓的高卡路里的“西方饮食”推动的。然而，也很明显，并不是每个高卡路里饮食的人都会变得肥胖。这表明饮食(环境)和个体的“基因组成”都影响了他们的身体组成(即脂肪与瘦身质量)。基因是我们DNA中的功能单位，它是一张“基因蓝图”，指示我们制造不同的蛋白质，这些蛋白质是我们身体所有细胞合成和执行其功能所必需的。在这个项目中，我们的目标是阐明决定身体如何对高卡路里饮食做出反应的基因。令人兴奋的是，我们最近的实验表明，特定基因的缺失可以防止西方饮食诱导的肥胖和与肥胖相关的代谢变化，如肝脏脂肪堆积(非酒精性脂肪性肝病的特征)和胰岛素抵抗(2型糖尿病的特征)。我们认为，这个基因在西方饮食中起着特殊的作用，因为它的缺失不会影响“正常”卡路里饮食的身体成分或新陈代谢。有趣的是，这种影响只在男性身上出现，这表明性别之间存在差异，这在人身上也可以观察到。因此，我们的目标是通过深入研究在缺乏该基因的情况下发生的变化来确定该基因是如何控制身体成分的：尤其是，我们对后续的初步研究感兴趣，这些研究表明，该基因可能会提高代谢率，从而导致更多的卡路里被“燃烧”。我们认为，这些变化是我们的基因作为其他基因的主要“调节器”的功能的结果，通过它控制细胞中不同成分的何时、何地和多少被制造。这就决定了细胞的功能及其适应不同“环境”影响的能力(如饮食)。因此，我们将不仅确定哪些细胞受到影响，还将确定这些细胞中的哪些细胞功能受到影响。最后，我们将确定这些细胞中哪些基因的调控发生了变化。这些信息是有用的，因为了解事物如何工作的细节是未来任何尝试和寻找新的治疗方法的重要的第一步，这些治疗方法可以操纵影响饮食引起的肥胖的途径。最后，由于我们的基因是一大类功能相关的基因(人类中的&gt；1000个家庭成员)中一个鲜为人知的例子，我们的结果可能与许多其他疾病(例如神经、生殖、致癌)有关，在这些疾病中，这类蛋白质起着因果作用。

Obesity is a major problem world-wide with 1 in 3 adults being overweight and 1 in 8 obese, equating to >600 million people worldwide. This growing epidemic of obesity represents a massive and rapidly growing health and economic burden for the UK (62.9% of adults in England were overweight or obese in 2015, an increase of 14.9% since 1993), as obesity is associated with serious health issues such as type 2 diabetes, heart disease and stroke. Moreover, there is growing evidence that obesity in pregnant women can affect the lifelong health of their babies, increasing their risk of becoming obese and having cardiovascular disease. This increase in obesity is driven largely by the increasing adoption of a so-called "Western diet" that is high in calories. However, it is also clear that not everyone on high calorie diets will become obese. This suggests that both diet (environment) and the "genetic make-up" of individuals contribute to their body composition (i.e. fat versus lean mass). Genes are functional units within our DNA that serve as a "genetic blueprint" for instructions to make the different proteins that are required for all the cells of our bodies to be made and carry out their functions. In this project, we aim to shed light on the genes that determine how the body responds to high calorie diets. Excitingly, our recent experiments show that deletion of a particular gene provides protection against Western diet-induced obesity and the metabolic changes that are associated with obesity such as accumulation of fat in the liver (a hallmark of non alcoholic fatty liver disease) and insulin resistance (a hallmark of type 2 diabetes). We propose that this gene plays a specific role in responding to the Western diet, as its loss did not affect body composition or metabolism on a "normal" calorie diet. Intriguingly, this effect was only seen in males, suggesting a difference between the sexes, which is also observed in people. Thus we aim to determine how this gene is controlling body composition by performing an in-depth study of the changes that occur in the absence of this gene: in particular, we are interested in following up our pilot studies that suggest it may increase the metabolic rate and therefore result in more calories being "burnt". We propose that these changes are a consequence of the function of our gene as a master "regulator" of other genes whereby it controls when, where and how much of the different components of cells are made. This then determines the function of cells and their ability to adapt to different "environmental" effects (e.g. diet). Therefore, we will determine not only which cells are affected, but also which cellular function within these cells is affected. Finally, we will then determine the genes within these cells that show changes in their regulation. This information is useful, as understanding the details of how things work is an important first step to any future efforts to try and find novel treatments that can manipulate the pathways that influence diet induced obesity. Lastly, because our gene is an example of a large class of functionally related genes (>1,000 family members in humans) that are poorly understood, our results can have relevance to many other diseases (e.g. neurological, reproductive, oncogenic) in which this class of proteins plays a causal role.