Molecular Characterization of New Selective Peroxisome Proliferator–Activated Receptor γ Modulators With Angiotensin Receptor Blocking Activity

Molecular Characterization of New Selective Peroxisome Proliferator–Activated Receptor γ Modulators With Angiotensin Receptor Blocking Activity Michael Schupp 1 , Markus Clemenz 1 , Romain Gineste 2 , Henning Witt 1 3 , Jürgen Janke 4 , Stephane Helleboid 2 , Nathalie Hennuyer 5 , Patricia Ruiz 1 3 , Thomas Unger 1 , Bart Staels 5 and Ulrich Kintscher 1 1 Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany 2 GENFIT, Parc Eurasante, Loos, France 3 Max-Planck Institute for Molecular Genetics, Berlin, Germany 4 Franz Volhard Clinic, HELIOS Hospital Berlin, Charité Campus Buch, Charité-Universitätsmedizin Berlin, Berlin, Germany 5 Department of Atherosclerose, Faculty of Pharmacy, Institute Pasteur Lille, University Lille II, UR 545 Institut National de la Santé et de la Recherche Médicale, Lille, France Address correspondencereprint requests to Ulrich Kintscher, MD, Center for Cardiovascular Research, Institute of PharmacologyToxicology, CCM Charité-Universitätsmedizin Berlin, Hessische Str., 3-4 10115 Berlin, Germany. E-mail: ulrich.kintscher{at}charite.de Abstract Selective peroxisome proliferator–activated receptor (PPAR) γ modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPARγ-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARγ protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identifies two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPAR