Development of an ex vivo system to assess murine adipocyte differentiation

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MRC : Tanyel Ashik : MR/N013700/1Under healthy conditions, our body's fat cells act as important reservoirs to store energy, and they can also release hormones that influence how much we eat and how different cells in our body store nutrients. However, during the development of obesity, the capacity for these fat cells to store excess fat becomes impaired, as does the types of factors released by fat cells. This leads to profound problems with our normal regulations of blood sugar levels and increases the risk for developing other health conditions such as type 2 diabetes and cardiovascular diseases. There is therefore a need for effective long-term therapies to promote weight loss.Various proteins that influence the growth and development of fat cells have been identified. One such factor is 14-3-3zeta, a unique protein that can help to direct where proteins go in a cell. The host lab previously found that when 14-3-3zeta is deleted, this blocked the growth of fat cells, but unexpectedly, they have recently found that reducing 14-3-3zeta levels in fat cells causes them to lose their identity and revert to an immature state. While it was initially thought that 14-3-3zeta is expressed in every cell, this is not the case, especially in adipose tissue of mice. This suggests that a specific group of fat cells will lose their maturity if 14-3-3zeta levels are reduced, and whether this will have implications on overall metabolic health is not known. This will be addressed in the current project, which will use genetically modified mice expressing fluorescent proteins that allow purification of 14-3-3zeta-positive and 14-3-3zeta-negative fat cells from adipose tissues, and it will be determined if these different groups of fat cells behave differently. We will measure the expression of various genes and explore if the cells are functionally different. When fat cells are removed from adipose tissue, they cannot survive for extended periods of time so we will also develop a new method to promote the long-term culture of these different populations of fat cells to increase our ability to properly study them.The benefits of this research are two-fold: in the short term it will improve our understanding of the complexity of fat cell biology and in the longer term this advancement in knowledge may lead to the development of new approaches to treat obesity, a chronic disease that continues to increase in worldwide prevalence.