Defining the Role of the Human Lipodystrophy Protein Seipin in Adipose Tissue Development and Metabolic Disease.

Nearly 1 in 4 adults in the UK is obese so obesity represents a major medical and economic challenge of the 21st century. Obesity is a substantial risk factor for the development of a number of serious metabolic diseases, including cardiovascular disease and type 2 diabetes, and also certain cancers. This illustrates the personal and national health implications of the current obesity crisis. Unfortunately, the paucity of effective obesity drug therapies highlights the need for a greater understanding of the biological systems that regulate body weight and how obesity leads to the development of metabolic diseases.

The co-incidence of obesity with metabolic diseases might make one think that inhibiting the development of fat (adipose) tissue would be a useful therapy. However, we know from patients unable to make fat tissue (lipodystrophy) that this is not the case. Rather, adipose tissue is a critical safe store for dietary nutrients, especially fat. When this is absent the fat instead accumulates in other tissues causing their dysfunction and resulting in metabolic disease more severe than that seen in obese individuals. We now know that, paradoxically, similar mechanisms may cause metabolic disease in common obesity. Here, whilst fat tissue is abundant, the fat cells within the tissue are dysfunctional and cannot store and release the dietary nutrients as they should. Again this leads to their accumulation in other tissues and so metabolic disease. It is now clear that about 10% of fat cells in humans are renewed each year. If we could make these new cells function better, and/or improve the function of existing fat cells we could significantly reduce metabolic disease in common obesity.

This project focuses on a protein called seipin, which when disrupted causes lipodystrophy in humans. Therefore, we know it is essential for human fat tissue development and function. We know very little about what seipin does but if we can work this out we will learn more about the process of fat cell formation and maybe even alter seipin's actions to treat metabolic disease by improving the function of fat cells.

We know that losing seipin prevents humans from making fat entirely. However, we don't know if this is because it is needed in the developing early embryo to make the stem cells that will later become fat cells, or if it is instead needed to allow the stem cells to mature into fat cells when the fat tissue appears later in development. In addition we do not know if seipin is needed for the normal renewal of fat cells in adults or to allow the increased fat cell number that happens when adults gain weight in obesity. This project will aim to answer these questions. State of the art methods will also allow us to determine exactly what seipin does inside the developing fat cell and will show us more about why seipin is so important for fat cell formation.

Overall we aim to identify the precise functions of seipin, which may allow us to find ways to modify its function. Importantly we will see what the effects of doing this in humans might be and so whether this might provide novel therapies to treat the rising epidemic of obesity associated diseases.

The incidence of obesity has increased dramatically and is linked to the development of conditions such as diabetes and cardiovascular disease. Adipocyte dysfunction is believed to significantly contribute to the development of metabolic disease in obesity. Hence, understanding how metabolically active adipocytes form may suggest new ways to beneficially manipulate newly generated or pre-existing adipocytes. As 10% of adipocytes in the human body are renewed each year, just targeting these newly developing cells could improve metabolic health. The overall aim of this study is to increase our understanding of adipocyte development and function and identify potential new therapeutic targets. Our approach is to focus on a protein called seipin, encoded by the gene BSCL2. Disruption of seipin causes a near complete absence of fat tissue in affected individuals, representing the most severe and selective form of this rare condition. Despite its critical role in fat development we know relatively little about what seipin does in developing adipocytes. If we can define how it regulates this process this could suggest novel future therapeutic targets.
Using cutting edge inducible knockout technologies we will define when during development seipin plays its critical role in fat development. We will also determine whether seipin is required for normal adipocyte turnover in adults and/or is needed to increase the number of adipocytes during obesity. In all cases we will define the metabolic consequences of losing seipin at these different developmental stages. Finally we will investigate the molecular mechanisms via which seipin may regulate adipogenesis. Together this will provide novel fundamental insights into the processes controlling fat cell development. It will also demonstrate whether altering the function of seipin, or the pathways it regulates, could be therapeutically useful for treating obesity related metabolic disease.

Obesity is a major health problem in the UK, leading to increased risk of disease and a health service burden in excess of a half billion pounds a year in direct costs. Current pharmacological therapies are extremely limited and so the identification of new potential therapeutic avenues are essential.

The work proposed aims to understand when and why the human lipodystrophy protein seipin is essential for human fat development and may uncover novel pathways via which adipocyte development and function might be regulated. This has the power to reveal new targets for the development of molecular or pharmacological therapies for the treatment of insulin resistance, obesity and metabolic disease.

The majority of the work addresses the fundamental questions regarding the molecular mechanisms of adipogenesis, adipocyte biology and adipose tissue development. When amenable and relevant pathways are identified through these studies, therapeutic drugs are likely to be 10 years or more from clinical use.

More acutely, any insights gained into novel regulators of adipogenesis may reveal new candidates to be screened in individuals with unsolved lipodystrophy or who appear likely to have severe monogenic forms of insulin resistance or obesity. As such it may be valuable in genetic diagnosis of these individuals, subsequently aiding their appropriate treatment.

Data obtained regarding altered serum biochemistry or peptides and intracellular lipid species or gene expression in the disease models tested may also suggest novel biomarkers for metabolic disease. Whilst not providing a cure, these could represent valuable diagnostic tools which would be available within a much shorter time frame of 3-5 years

Intellectual property arising from the proposed research will be exploited with help from the Research and Innovation Team at the University of Aberdeen who have extensive expertise in advising on how best to do this (http://www.abdn.ac.uk/research-innovation/). The proposed research may inform and benefit the pharmaceutical sector through access to new knowledge and technology development. Thus it has the potential to enhance the knowledge economy and economic competitiveness of the UK.

On an individual level, the post-doctoral research associate who will be recruited to work on this project will gain or strengthen technical skills in a wide range of molecular, cellular and in vivo techniques and also increase their experience of presentation to large and small audiences and public engagement. Hence they will gain valuable training that will benefit them and their future employers whether in academia, the pharmaceutical industry or many other employment sectors.

The research is also readily accessible to the general public, because of its immediate relevance to reducing obesity, improving health, living longer and enhancing quality of life. The project therefore provides an excellent vehicle for increasing public engagement and understanding of this common condition.