A novel non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand UHC1 blocks PPARγ phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity.

Abstract	Thiazolidinedione class of anti-diabetic drugs which are known as peroxisome proliferator-activated receptor γ (PPARγ) ligands have been used to treat metabolic disorders, but thiazolidinediones 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 UNIST HYUNDAI Compound 1 (UHC1) that binds tightly to PPARγ without the classical agonism and which blocks cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation. We modified the non-agonist PPARγ ligand SR1664 chemically to improve its solubility 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 Ser-273. Surprisingly, UHC1 treatment effectively ameliorated the inflammatory response both in vitro and in high-fat diet-fed mice. Furthermore, UHC1 treatment dramatically improved insulin sensitivity in high-fat diet-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.
Authors	Sun-Sil Choi, Eun Sun Kim, Minseob Koh, Soo-Jin Lee, Donghyun Lim, Yong Ryoul Yang, Hyun-Jun Jang, Kyung-Ah Seo, Sang-Hyun Min, In Hee Lee, Seung Bum Park, Pann-Ghill Suh, Jang Hyun Choi
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 38 Pg. 26618-26629 (Sep 19 2014) ISSN: 1083-351X [Electronic] United States
PMID	25100724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References	(S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid 4'-((2,3-dimethyl-5-(pyridin-3-ylmethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylic acid Anti-Inflammatory Agents Benzoates Biphenyl Compounds Hypoglycemic Agents Indoles Inflammation Mediators PPAR gamma Cyclin-Dependent Kinase 5
Topics	3T3-L1 Cells Adipogenesis (drug effects) Animals Anti-Inflammatory Agents (chemistry, pharmacology) Benzoates (chemistry, pharmacology) Binding Sites Biphenyl Compounds (chemistry, pharmacology) Cyclin-Dependent Kinase 5 (physiology) Diabetes Mellitus, Experimental (drug therapy) Drug Evaluation, Preclinical HEK293 Cells Humans Hydrogen Bonding Hypoglycemic Agents (chemistry, pharmacology) Indoles (chemistry, pharmacology) Inflammation Mediators (metabolism) Insulin Resistance Male Mice Mice, Inbred C57BL Molecular Docking Simulation PPAR gamma (agonists, chemistry, metabolism) Phosphorylation Protein Binding Protein Processing, Post-Translational Rats, Sprague-Dawley

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