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Diabetes Publish Ahead of Print published online ahead of print August 17, 2007
DOI: 10.2337/db06-1734
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Original Research

S 26948, a new specific PPAR{gamma} modulator (SPPARM) with potent antidiabetic and antiatherogenic effects

M C Carmonaa, K Louchea, B Lefebvreb, A Pilonb, N Hennuyerc, V Audinot-Bouchezd, C Fievetc, G Torpierc, P Formstecherb, P Renarde, P Lefebvreb, C Dacquete, B Staelsc, L Casteillaa, and L Pénicauda

From the Consortium of the French Ministry of Research and Technology: "Molecules and New Therapeutic Targets" aUMR 5241 UPS-CNRS, IFR 31, BP84225, Toulouse
From the Consortium of the French Ministry of Research and Technology: "Molecules and New Therapeutic Targets" bU459 INSERM, Lille
From the Consortium of the French Ministry of Research and Technology: "Molecules and New Therapeutic Targets" cU545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille and University of Lille II, Lille
From the Consortium of the French Ministry of Research and Technology: "Molecules and New Therapeutic Targets" dDivision of Molecular and Cellular Pharmacology, Institut de Recherche Servier (IdRS), Croissy sur Seine
From the Consortium of the French Ministry of Research and Technology: "Molecules and New Therapeutic Targets" eDivision of Experimental Therapeutic and Division of External Chemistry, Institut de Recherches Internationales Servier (IRIS), Courbevoie, France

Correspondence: penicaud{at}toulouse.inserm.fr

Key Words: Thiazolidinedione • obesity • diabetes • adipogenesis • atherosclerosis • coactivators • body weight • adipose tissue.

OBJECTIVE: Rosiglitazone displays powerful antidiabetic benefit but associated with increased body weight and adipogenesis. Keeping in mind the concept of Selective PPAR{gamma} Modulator (SPPARM), the aim of this study is to characterize the properties of a new PPAR{gamma} ligand, S 26948, with special attention in body weight gain.

RESEARCH DESING AND METHODS: We used transient transfection and binding assays to characterized the binding characteristics of S 26948, and GST pull-down experiments to find out its pattern of coactivator recruitment compared with Rosiglitazone. We also assessed its adipogenic capacity in vitro using the 3T3-F442A cell line, and its in vivo effects in ob/ob mice (for antidiabetic and antiobesity properties), and the homozygous human apolipoprotein (apo) E2 knock-in mice (E2-KI)(for antiatherogenic capacity).

RESULTS: S 26948 displayed pharmacological features of a high selective ligand for PPAR{gamma} with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared to Rosiglitazone, being unable to recruit DRIP205 or PGC-1{alpha}. In vivo experiments showed that S 26948 was as efficient in ameliorating glucose and lipid homeostasis as Rosiglitazone, but it did not increase body and white adipose tissue weights and improved lipid oxidation in liver. In addition, S 26948 represented one of the few molecules of the PPAR{gamma} ligand class which was able to decrease atherosclerotic lesions.

CONCLUSIONS: These findings establish S 26948 as a selective PPAR{gamma} ligand with distinctive coactivator recruitment, gene expression profile, reduced adipogenic effect and improved biological responses in vivo.


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Copyright © 2007 by the American Diabetes Association.