GQ-16, a Novel Peroxisome Proliferator-activated Receptor gamma (PPAR gamma) Ligand, Promotes Insulin Sensitization without Weight Gain

The recent discovery that peroxisome proliferator-activated receptor gamma (PPAR gamma) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPAR gamma activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPAR gamma. The structure of GQ-16 bound to PPAR gamma demonstrates that the compound utilizes a binding mode distinct from other reported PPAR gamma ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the beta-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPAR gamma-based therapeutics stabilize the beta-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPAR gamma modulators that retain antidiabetic actions while minimizing untoward effects.

MCT/CNPq/CTInfra/CTGrant

MCT/CNPq/CT-Infra/CT-Grant [620195/2008-8, 485811/2011-1]

Fundacao de Amparo a Pesquisa do Estado de Sao 598 Paulo (FAPESP)

Fundacao de Amparo a Pesquisa do Estado de Sao 598 Paulo (FAPESP) [2010/17048-8]

FAPESP

FAPESP [2010/08680-2, 2009/14108-2]

National Institutes of Health, NIGMS

National Institutes of Health, NIGMS

Howard Hughes Medical Institute

Howard Hughes Medical Institute

Office of Science, Office of Basic Energy Sciences, of the United States Department of Energy [DE-AC02-05CH11231]

Office of Science, Office of Basic Energy Sciences, of the United States Department of Energy