"Bruce Spiegelman at Dana-Farber was starting to uncover the fact that the phosphorylation of PPAR takes place in the very region where MRL-24, one of the partial agonists interacted," Griffin said. "I suggested that compounds like MRL24 might be better at antagonizing the cdk5 site given their strong interaction in this region of the receptor. For the new study, we provided significant amounts of compound to support the animal studies and provided an plausible mechanism for how partial agonists might recruit co-activator proteins to the cdk5 surface of PPARg."

While the team found that PPAR phosphorylation effects were reversed by both full and partial agonists, partial agonists indeed accomplished this as well or better than the full agonists. Mimicking the effects of just blocking the phosphorylation event by mutation of the site on the receptor showed improvements in the production of adiponectin.

The new study also suggests a unified framework for understanding the relationship between fat cell dysfunction in obesity and anti-diabetic therapies based on PPAR . In animal studies, high fat diets activate the cdk5 kinase, initiating phosphorylation, disrupting a number of key metabolic regulators including adiponectin and adipsin, a fat cell-selective gene whose expression is altered in obesity.

"The great paradox of this whole effort is we're targeting a receptor critical for fat production to offset the problem of fat overproduction," Griffin said. "Unfortunately, current drugs that target PPARg increase fat as one of their unwanted long-term side effects."

While the study is a big step forward, important questions still remain such as does a high fat diet and obesity lead to activation of cdk5 in non-fat tissues, Griffin said, since the negative effects of obesity extend far beyond metabolic syndrome to diseases like cancer and neurodegeneration.

The first authors of the study, "Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR by Cdk5," are Jang Hyun Choi, Alexander S. Banks Jennifer L. Estall, and Shingo Kajimura of the Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School. Other authors include Pontus Bostrom, Dina Laznik, Bruce M. Spiegelman and Jorge L. Ruas of the Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School; Michael J. Chalmers, Theodore M. Kamenecka of The Scripps Research Institute; and Matthias Bluher of the University of Leipzig, Germany.

Source: Scripps Research Institute