Delineating the regulation and function of gamma-synuclein in adipocyte lipid metabolism

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Obesity represents one of the biggest current medical challenges worldwide and so there is a clear need to find new potential therapies to combat this increasingly prevalent condition. Fat tissue is comprised of adipocytes which are cells specialised to allow the safe storage of fat in one large lipid droplet occupying most of the cell. The bigger the lipid droplet is the larger the fat cell becomes and the greater the overall mass of fat tissue. In obesity, it appears that the safe lipid storage capacity of fat tissue may be exceeded and lipids then instead go to other tissues causing harmful effects. Many prevalent diseases are linked to the negative effects of these lipids including diabetes, heart disease and some forms of dementia. We have recently found that inhibiting a protein called gamma-synuclein might prevent the development of obesity. The gamma-synuclein protein is particularly highly expressed in fat cells. In fat cells lacking gamma-synuclein the breakdown of the lipid droplet is increased. However, this does not cause a problematic rise in lipids going to other tissues because it seems that the lipid that comes from the lipid droplet in the fat cell can be preferentially burnt as a fuel to provide energy in a way that lipids from the diet are not. This burning of lipids particularly occurs in specialised brown fat cells which are capable of doing this and then dissipating the energy generated as heat. Activating this process is seen a potential way to treat obesity by effectively burning excess lipids and wasting energy. We have found that inhibiting gamma-synuclein may help brown fat cells to do this more efficiently. Therefore, overall the effect of gamma-synuclein inhibition may be both to break down fat stores and then to burn the lipid in the brown fat cells. In this study we aim to understand 1) how the gamma-synuclein gene is switched on and off in fat cells, 2) how precisely gamma-synuclein controls the breakdown of the lipid droplet and 3) how losing gamma-synuclein makes brown fat cells burn more lipids. All of these may suggest ways to change levels of gamma-synuclein or alter the way it works to reduce body weight and/or treat the diseases associated with obesity.