Elucidating the Function of BSCL2, a Critical Regulator of Human Fat Development

Given the high and increasing rates of obesity, the harmful effects of excess fat on health are well known. However, conditions in which fat mass is abnormally low (lipodystrophies) are much rarer and so receive far less attention. In fact, having either too much or too little body fat are each strongly associated with similar diseases such as diabetes and heart disease which are major causes of suffering and mortality. This shows that it is important for us to develop just the right amount of fat and for it to be able to work efficiently to store and release nutrients and secrete the hormones it produces appropriately. Increasing fat mass involves making new fat cells (adipocytes) from precursor cells, and carefully controlling this process is therefore critical for health. This work examines this process mainly using cells that can be turned into adipocytes in the lab and studying the genes that regulate this process. Specifically we are focussing on a gene called BSCL2 which we know is critical for making fat tissue in humans as its disruption causes almost complete lack of fat. We have recently discovered that this gene regulates the process of adipocyte formation but the precise mechanism by which it does this is not clear. This work aims to define how BSCL2 controls the formation of fat cells, to identify the proteins it interacts with to do this, and how BSCL2 itself is regulated. In this way we will learn much more about how fat cells develop. This information will not only be critical for ultimately finding ways to treat patients with this very specific, rare but devastating form of lipodystrophy, but is also extremely relevant to understanding the development and treatment of obesity.

Homozygous mutations in the gene BSCL2 cause the most severe form of congenital lipodystrophy, Berardinelli-Seip congenital lipodystrophy type 2, in which there is a near complete absence of adipose tissue. Remarkably, the mechanism whereby this occurs has remained unclear as very little is understood about the BSCL2 protein. The severity of the disease has led to speculation that BSCL2 may play a role in stem cell commitment to adipogenesis. However, the expression of BSCL2 in the brain has also led to suggestions of a centrally mediated role in fat formation. The first insights into the cellular function of BSCL2 have come through the recent identification of the yeast orthologue of BSCL2. Yeast lacking this gene fail to appropriately generate intracellular lipid droplets, and a similar phenotype was also described in fibroblasts isolated from a BSCL2 patient. However, this study did not elucidate the mechanism behind this phenomenon and the molecular role of BSCL2 remained unclear. We have now shown that BSCL2 is highly expressed in mature adipocytes, is induced during adipogenesis, and that BSCL2 expression is essential for adipocyte formation. This proposal aims to build on these data to more clearly define the role and regulation of BSCL2 in adipogenesis. Specifically the work will: 1. Characterise the effects of BSCL2 inhibition, determine how BSCL2 controls adipocyte formation, and delineate the transcriptional regulation of the BSCL2. Each of these may suggest therapeutic strategies for altering BSCL2 expression; 2. Identify new binding partners for BSCL2 and thereby give further insight into its function; 3. Attempt to rescue the effects of lipodystrophy-causing mutations in BSCL2 in vitro and so ultimately inform treatment of BSCL2 patients; 4. Determine whether polymorphisms in BSCL2 may influence adiposity and metabolic disease traits in the general population. This research will give exciting molecular insights into this devastating form of lipodystrophy. As BSCL2 is a key regulator of adipogenesis, a process whose perturbation is at the heart of other conditions of altered fat mass, this research is also of major relevance to highly prevalent disorders including obesity and associated conditions such as diabetes and cardiovascular disease.