S 26948: a New Specific Peroxisome Proliferator Activated Receptor {gamma} Modulator With Potent Antidiabetes and Antiatherogenic Effects

doi:10.2337/db06-1734

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S 26948

a New Specific Peroxisome Proliferator–Activated Receptor ${gamma}$ Modulator With Potent Antidiabetes and Antiatherogenic Effects

Maria Carmen Carmona¹, Katie Louche¹, Bruno Lefebvre², Antoine Pilon³, Nathalie Hennuyer³, Véronique Audinot-Bouchez⁴, Catherine Fievet³, Gérard Torpier³, Pierre Formstecher², Pierre Renard⁵, Philippe Lefebvre², Catherine Dacquet⁵, Bart Staels³, Louis Casteilla¹, Luc Pénicaud¹ on behalf of the Consortium of the French Ministry of Research and Technology

¹ UMR 5241, UPS-CNRS, IFR 31, BP84225, Toulouse, France
² U459 INSERM, Lille, France
³ U545 INSERM, Département d’Athérosclérose, Institut Pasteur de Lille and University of Pharmacy Lille II, Lille, France
⁴ Division of Molecular and Cellular Pharmacology, Institut de Recherche Servier, Croissy sur Seine, France
⁵ Division of Experimental Therapeutic and Division of External Chemistry, Institut de Recherches Internationales Servier, Courbevoie, France

Address correspondence and reprint requests to Luc Pénicaud, UMR 5241 CNRS-UPS, IFR 31, BP84225, 31432 Toulouse Cedex 4, France. E-mail: penicaud{at}toulouse.inserm.fr

Abbreviations: Apo, apolipoprotein; DMEM, Dulbecco's modified Eagle's medium; FFA, free fatty acid; IDL, intermediate-density lipoprotein; iWAT, inguinal white adipose tissue; NEFA, nonesterified fatty acid; PGC, peroxisome proliferator–activated receptor ${gamma}$ coactivator; PPAR, peroxisome proliferator–activated receptor; RXR, retinoic X receptor; SPPARM, selective PPAR ${gamma}$ modulator; TNF, tumor necrosis factor; TZD, thiazolidinedione; UCP, uncoupled protein; WAT, white adipose tissue

OBJECTIVE—Rosiglitazone displays powerful antidiabetesbenefits but is associated with increased body weight and adipogenesis.Keeping in mind the concept of selective peroxisome proliferator–activatedreceptor (PPAR) ${gamma}$ modulator, the aim of this study was to characterizethe properties of a new PPAR ${gamma}$ ligand, S 26948, with special attentionin body-weight gain.

RESEARCH DESIGN AND METHODS—We used transient transfectionand binding assays to characterized the binding characteristicsof S 26948 and GST pull-down experiments to investigate itspattern of coactivator recruitment compared with rosiglitazone.We also assessed its adipogenic capacity in vitro using the3T3-F442A cell line and its in vivo effects in ob/ob mice (forantidiabetes and antiobesity properties), as well as the homozygoushuman apolipoprotein E2 knockin mice (E2-KI) (for antiatherogeniccapacity).

RESULTS—S 26948 displayed pharmacological features ofa high selective ligand for PPAR ${gamma}$ with low potency in promotingadipocyte differentiation. It also displayed a different coactivatorrecruitment profile compared with rosiglitazone, being unableto recruit DRIP205 or PPAR ${gamma}$ coactivator-1 ${alpha}$ . In vivo experimentsshowed that S 26948 was as efficient in ameliorating glucoseand lipid homeostasis as rosiglitazone, but it did not increasebody and white adipose tissue weights and improved lipid oxidationin liver. In addition, S 26948 represented one of the few moleculesof the PPAR ${gamma}$ ligand class able to decrease atherosclerotic lesions.

CONCLUSIONS—These findings establish S 26948 as a selectivePPAR ${gamma}$ ligand with distinctive coactivator recruitment and geneexpression profile, reduced adipogenic effect, and improvedbiological responses in vivo.