Controlling a Fat-Regulating Protein Dramatically Increases Insulin Sensitivity

PPARy is a protein that regulates the body's production of fat cells. However, obesity can modify how PPARy works, leading to decreased insulin sensitivity and the development of metabolic syndrome. (Metabolic syndrome is the cluster of factors, including insulin resistance, overweight, high blood pressure, and abnormal blood sugar levels, that is a precursor to type 2 diabetes.)

But now a joint team of researchers from The Scripps Research Institute in San Diego and the Dana-Farber Cancer Institute at Harvard University in Cambridge has found a way to control the adverse changes in PPARy brought on by obesity.

One of those changes is phosphorylation, when an enzyme called cdk5 kinase adds a phosphate group to PPARy. That addition causes PPARy to alter the expression of several genes, including one that regulates production of adiponectin, a protein essential to insulin sensitivity. 

The challenge for the scientists was to find a way to change PPARy back to its normal state without inducing it to overproduce fat cells. They knew from a previous study that an agonist, a compound that makes cells respond in certain ways, interacted with the region of PPARy known to regulate fat generation. The agonist in that case was a full agonist, meaning that it was able to easily combine with a receptor in that region of PPARy and activate it to do a certain thing-in this case, not generate fat cells.

The researchers wondered if partial agonists-chemical agents that have only partial effects on certain cell receptors-could be used to counteract the insulin-suppressing effects of phosphorylation on PPARy without the side effect of ramping up fat cell production.

They found that while partial agonists did not interact with the PPARy receptor that governs fat cell production, one, called MRL24, worked  extremely well in the exact region of PPARy where phosphorylation takes place. By altering and diminishing that region's receptiveness to  phosphorylation, MRL24 allowed PPARy to increase the production of adiponectin.

Those findings, which open the door to learning how to fully manipulate PPARy, could lead to drugs that reduce the risk of developing type 2 diabetes and cardiovascular problems. If PPARy can be prevented in obese people from losing its ability to direct the production of adiponectin, it could become a significant therapy in treating the effects of extreme overweight.

Thank you Patrick Totty