S 26948

a New Specific Peroxisome Proliferator–Activated Receptor γ Modulator With Potent Antidiabetes and Antiatherogenic Effects

  1. Maria Carmen Carmona1,
  2. Katie Louche1,
  3. Bruno Lefebvre2,
  4. Antoine Pilon3,
  5. Nathalie Hennuyer3,
  6. Véronique Audinot-Bouchez4,
  7. Catherine Fievet3,
  8. Gérard Torpier3,
  9. Pierre Formstecher2,
  10. Pierre Renard5,
  11. Philippe Lefebvre2,
  12. Catherine Dacquet5,
  13. Bart Staels3,
  14. Louis Casteilla1,
  15. Luc Pénicaud1 and
  16. on behalf of the Consortium of the French Ministry of Research and Technology
  1. 1UMR 5241, UPS-CNRS, IFR 31, BP84225, Toulouse, France
  2. 2U459 INSERM, Lille, France
  3. 3U545 INSERM, Département d’Athérosclérose, Institut Pasteur de Lille and University of Pharmacy Lille II, Lille, France
  4. 4Division of Molecular and Cellular Pharmacology, Institut de Recherche Servier, Croissy sur Seine, France
  5. 5Division of Experimental Therapeutic and Division of External Chemistry, Institut de Recherches Internationales Servier, Courbevoie, France
  1. 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

Abstract

OBJECTIVE—Rosiglitazone displays powerful antidiabetes benefits but is associated with increased body weight and adipogenesis. Keeping in mind the concept of selective peroxisome proliferator–activated receptor (PPAR)γ modulator, the aim of this study was to characterize the properties of a new PPARγ ligand, S 26948, with special attention in body-weight gain.

RESEARCH DESIGN AND METHODS—We used transient transfection and binding assays to characterized the binding characteristics of S 26948 and GST pull-down experiments to investigate 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 antidiabetes and antiobesity properties), as well as the homozygous human apolipoprotein E2 knockin mice (E2-KI) (for antiatherogenic capacity).

RESULTS—S 26948 displayed pharmacological features of a high selective ligand for PPARγ with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPARγ coactivator-1α. 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 PPARγ ligand class able to decrease atherosclerotic lesions.

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

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 17 August 2007. DOI: 10.2337/db06-1734.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received December 14, 2006.
    • Accepted August 10, 2007.
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  1. Diabetes vol. 56 no. 11 2797-2808
  1. All Versions of this Article:
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