I used to work on compounds targeting the PPAR family (and nuclear receptors in general). I knew nothing about the field when I started, which is the traditional situation a medicinal chemist is in, but I picked it up. And picked it up. . .and picked up still more information, on and on, as it dawned on me that the whole field was quite possibly beyond our ability to deal with in an organized fashion.
Not that people didn't try, famously Glaxo. They cranked up a huge effort to go after these targets with the full toolbox - structure, pharmacology, med-chem, animal models, the lot. Merck and others did the same, but Glaxo's team were out there front and center at every conference, presenting data and mentioning in asides that they had X dozen crystal structures of that receptor, and this-many compounds heading into development, and so on. Very little has emerged out on the money-making end from all this work, by all the companies who've tried it. Avandia (rosiglitazone) and Actos (pioglitazone) are still the only PPAR-targeting drugs on the market, with Avandia in serious trouble, and they were both developed before anyone knew what their target was.
But there's absolutely no doubt that PPAR subtypes are major metabolic players; it's just that we don't quite know how to untangle the huge number of effects they have. Now a paper from one of the longtime leaders in the field, Bruce Spiegelman, might restore some order. And it does so in an unexpected way.
Upstream of all the hideously complex transcriptional effects, subtly modulated by ligand, by cell type, by time of day and who know what else, Spiegelman's groups has found that it's the phosphorylation of PPAR-gamma by the kinase CDK5 that might be the key. That doesn't alter the broad strokes of transcription, but it does alter specific genes that are associated with obesity and the metabolic syndrome. (It's known that the PPARs associate with a host of other protein cofactors, and this phosphorylation probably affects some protein-potein binding surface).
High-fat diets in rodents crank up CDK5 activity, and a whole list of effective PPAR compounds, it turns out, keep the receptor from being phosphorylated by it. Moreover, insulin sensitivity correlates quite well with the degree of phosphorylation. It really does look as if the code has been cracked - we may finally know what the primary PPAR-linked event is that affects type II diabetes. So, forget all those other assays: just measure the amount of serine-273 phosphorylation and you've done what you need to do?
This work has doubtless caused plenty of people in the metabolic disease field to drop whatever they were holding and start thinking things all over again. There are a lot of questions to answer: what happens if you dose a CDK5 inhibitor? In what other tissues does a high-fat diet alter CDK5 activity? Could you get all the insulin-sensitization effects of a glitazone drug without the side effects, by targeting a drug development program differently? Does CDK5 have anything to do with the cardiac side effects that everyone's so worried about with Avandia? And so on. It's a great result, one of those papers where you really come away knowing something crucial that you didn't before.