The receptor, called PPAR-gamma, resembles several other receptor proteins that bind to small hormones. In fat cells, this receptor influences a variety of processes, including sugar metabolism and fat cell proliferation, by turning specific genes on and off. Chemicals that can bind to the receptor increase insulin's ability to lower blood sugar in the body. That action is crucial to controlling adult-onset diabetes, which results not from a lack of insulin, but from the inability of cells to heed insulin's signals, says senior author Mitchell A. Lazar, MD, PhD, professor of medicine and genetics at Penn. More than 15 million Americans are thought to suffer from adult-onset diabetes, which typically develops after age 40.
Half are unaware they have the disease, which is also a risk factor for heart disease and stroke.
And, TZDs further encourage obesity by repressing the gene for leptin, an important weight-regulation factor. His group's recent findings represent an important advance toward that goal. This distant site, Lazar says, provides an additional target for the next generation of diabetes drugs to hit. If compounds can be found that affect this regulatory site, they may lead to diabetes drugs with fewer side effects, according to Lazar. At any given time, half of the PPAR-gamma receptors in fat cells are phosphorylated, Lazar notes.