Fat’s proteomic fingerprint sheds light on Type 2 diabetes

Fat cells aren’t just for show, even if most of us don’t like showing them. They also play an important role in metabolism, particularly of glucose, and dysfunction in fat cells is one of the contributing factors to Type 2 diabetes.

Now a new study by researchers at Sydney’s Garvan Institute has delved into the proteomics of the fat cell’s outer plasma membrane to see how insulin interacts with the fat cell.

The study, which took two years to compile and analyse, used quantitative proteomics to define the protein composition of the PM, finding 486 proteins, 98 of which are potentially newly discovered.

Some of the proteins, including an “unusually high” number of hydrolases have no known function as yet. They also found several novel proteins that are responsive to insulin.

“This is very novel – a detailed study of the plasma membrane has not been done on any cell, let alone a fat cell,” said Dr Matthew Prior, a co-author who works in the Diabetes Program at the Garvan.

“Proteins carry out the work of the cell, and their precise location tells us a lot about what they do. This study highlights the proteins that are either embedded within, or have a strong association with, the plasma membrane. It reveals aspects of function, which in some cases was a mystery until now.

“We isolated cells and brought them to basal level – so we could work out the proteome of the cell surface in the absence of stimulation.

“By then looking at the cell surface in the presence of insulin, we could see which proteins changed. Some proteins moved away from the cell surface, while other proteins moved towards it. A good example is the glucose transporter GLUT 4 – which in response to insulin moves to the cell surface to facilitate the entry of glucose into the cell.

“GLUT 4 was our positive control – as we already know that it’s regulated by insulin. As well as seeing a rise in GLUT 4 levels, we also saw a number of other proteins, not previously known to be insulin-responsive, move to the cell surface.

“It’s already known that when you put insulin onto a cell, the pH goes up. One of the abundant proteins we identified is involved with intracellular pH.

“Metabolism of food – facilitated by insulin – generates lactic acid and other acidic metabolites. Because of this, we surmise that insulin increases the cell’s pH as a way of buffering it against acidity.

“In all, there were around 10 proteins that robustly changed with insulin exposure.”

Most importantly, the study gives the science community the fat cell fingerprint, the receptors on the surface of a fat cell being very different from those found on a muscle cell or a bone cell.

This kind of cellular specificity is important in the development of new drug targets, the best of which are cell surface proteins.

The study was published in the Journal of Proteome Research.