AIMS/HYPOTHESIS: Existing thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor γ (PPARγ) ligands that retain the benefits in improving insulin resistance but with reduced side effects. METHODS: We used AlphaScreen assay to screen for new PPARγ ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARγ. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARγ complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs. RESULTS: We found that the antibiotic ionomycin is a novel modulating ligand for PPARγ. Both the transactivation and binding activity of PPARγ by ionomycin can be blocked by PPARγ specific antagonist GW9662. Ionomycin interacts with the PPARγ ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo. CONCLUSIONS/ INTERPRETATION: Our studies suggest that ionomycin may represent a unique template for designing novel PPARγ ligands with advantages over current TZD drugs.
AIMS/HYPOTHESIS: Existing thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor γ (PPARγ) ligands that retain the benefits in improving insulin resistance but with reduced side effects. METHODS: We used AlphaScreen assay to screen for new PPARγ ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARγ. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARγ complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs. RESULTS: We found that the antibiotic ionomycin is a novel modulating ligand for PPARγ. Both the transactivation and binding activity of PPARγ by ionomycin can be blocked by PPARγ specific antagonist GW9662. Ionomycin interacts with the PPARγ ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo. CONCLUSIONS/ INTERPRETATION: Our studies suggest that ionomycin may represent a unique template for designing novel PPARγ ligands with advantages over current TZD drugs.
Authors: Yong Li; Mihwa Choi; Greg Cavey; Jennifer Daugherty; Kelly Suino; Amanda Kovach; Nathan C Bingham; Steven A Kliewer; H Eric Xu Journal: Mol Cell Date: 2005-02-18 Impact factor: 17.970
Authors: Tamara Allen; Fang Zhang; Shonna A Moodie; L Edward Clemens; Aaron Smith; Francine Gregoire; Andrea Bell; George E O Muscat; Thomas A Gustafson Journal: Diabetes Date: 2006-09 Impact factor: 9.461
Authors: Christopher Weidner; Jens C de Groot; Aman Prasad; Anja Freiwald; Claudia Quedenau; Magdalena Kliem; Annabell Witzke; Vitam Kodelja; Chung-Ting Han; Sascha Giegold; Matthias Baumann; Bert Klebl; Karsten Siems; Lutz Müller-Kuhrt; Annette Schürmann; Rita Schüler; Andreas F H Pfeiffer; Frank C Schroeder; Konrad Büssow; Sascha Sauer Journal: Proc Natl Acad Sci U S A Date: 2012-04-16 Impact factor: 11.205
Authors: R T Gampe; V G Montana; M H Lambert; A B Miller; R K Bledsoe; M V Milburn; S A Kliewer; T M Willson; H E Xu Journal: Mol Cell Date: 2000-03 Impact factor: 17.970
Authors: Liliane Michalik; Johan Auwerx; Joel P Berger; V Krishna Chatterjee; Christopher K Glass; Frank J Gonzalez; Paul A Grimaldi; Takashi Kadowaki; Mitchell A Lazar; Stephen O'Rahilly; Colin N A Palmer; Jorge Plutzky; Janardan K Reddy; Bruce M Spiegelman; Bart Staels; Walter Wahli Journal: Pharmacol Rev Date: 2006-12 Impact factor: 25.468
Authors: A Zanchi; M Maillard; F R Jornayvaz; M Vinciguerra; P Deleaval; J Nussberger; M Burnier; A Pechere-Bertschi Journal: Diabetologia Date: 2010-04-23 Impact factor: 10.122
Authors: Yong Li; Jifeng Zhang; Francisco J Schopfer; Dariusz Martynowski; Minerva T Garcia-Barrio; Amanda Kovach; Kelly Suino-Powell; Paul R S Baker; Bruce A Freeman; Y Eugene Chen; H Eric Xu Journal: Nat Struct Mol Biol Date: 2008-07-06 Impact factor: 15.369
Authors: Wei Yi; Jingjing Shi; Guanguan Zhao; X Edward Zhou; Kelly Suino-Powell; Karsten Melcher; H Eric Xu Journal: Sci Rep Date: 2017-01-27 Impact factor: 4.379
Authors: Vladimir V Sobolev; Ekaterina Tchepourina; Irina M Korsunskaya; Natalia A Geppe; Svetlana N Chebysheva; Anna G Soboleva; Alexandre Mezentsev Journal: Int J Mol Sci Date: 2022-08-26 Impact factor: 6.208