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

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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.