A novel non-agonist PPAR{gamma} ligand UHC1 blocks PPAR{gamma} phosphorylation by CDK5 and improves insulin sensitivity [Molecular Bases of Disease]

August 6th, 2014 by Choi, S. S., Kim, E. S., Koh, M., Lee, S.-J., Lim, D., Yang, Y. R., Jang, H.-J., Seo, K.-a., Min, S.-H., Lee, I. H., Park, S. B., Suh, P.-G., Choi, J. H.

Thiazolidinedione (TZD) class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but TZDs can also cause several severe side effects, including congestive heart failure, fluid retention, and weight gain. In this study, we describe a novel synthetic PPARγ ligand (UHC1) that binds tightly to PPARγ without the classical agonism and which blocks CDK5-mediated PPARγ phosphorylation. We modified the non-agonist PPARγ ligand SR1664 chemically to improve its solubility and PPARγ binding affinity and then developed a novel PPARγ ligand, UHC1. According to our docking simulation, UHC1 occupied the ligand-binding site of PPARγ with a higher docking score than SR1664. In addition, UHC1 more potently blocked CDK5-mediated PPARγ phosphorylation at Ser273. Surprisingly, UHC1 treatment effectively ameliorated the inflammatory response both in vitro and in HFD-fed mice. Furthermore, UHC1 treatment dramatically improved insulin sensitivity in HFD-fed mice without causing fluid retention and weight gain. Taken together, compared with SR1664, UHC1 exhibited greater beneficial effects on glucose and lipid metabolism by blocking CDK5-mediated PPARγ phosphorylation, and these data indicate that UHC1 could be a novel therapeutic agent for use in type 2 diabetes and related metabolic disorders.
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