title: S 26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects.
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)gamma modulator, the aim of this study was to characterize the properties of a new PPARgamma ligand, S 26948, with special attention in body-weight gain.
  
  
  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 knocking mice (E2-KI) (for antiatherogenic capacity).
  
  
  RESULTS
  S 26948 displayed pharmacological features of a high selective ligand for PPARgamma with low potency in promoting adipocyte differentiation. It also displayed a different coactivator recruitment profile compared with rosiglitazone, being unable to recruit DRIP205 or PPARgamma coactivator-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 PPARgamma ligand class able to decrease atherosclerotic lesions.
  
  
  CONCLUSIONS
  These findings establish S 26948 as a selective PPARgamma ligand with distinctive coactivator recruitment and gene expression profile, reduced adipogenic effect, and improved biological responses in vivo.
authors: UMR 5241, CNRS-UPS, IFR 31, BP84225, 31432 Toulouse Cedex 4, France.
authors: Maria Carmen
authors: MC
authors: Carmona
authors: Katie
authors: K
authors: Louche
authors: Bruno
authors: B
authors: Lefebvre
authors: Antoine
authors: A
authors: Pilon
authors: Nathalie
authors: N
authors: Hennuyer
authors: Véronique
authors: V
authors: Audinot-Bouchez
authors: Catherine
authors: C
authors: Fievet
authors: Gérard
authors: G
authors: Torpier
authors: Pierre
authors: P
authors: Formstecher
authors: Pierre
authors: P
authors: Renard
authors: Philippe
authors: P
authors: Lefebvre
authors: Catherine
authors: C
authors: Dacquet
authors: Bart
authors: B
authors: Staels
authors: Louis
authors: L
authors: Casteilla
authors: Luc
authors: L
authors: Pénicaud
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D019556:COS Cells; D002462:Cell Membrane / Q000502:physiology; D002522:Chlorocebus aethiops; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008024:Ligands; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D047490:Retinoid X Receptor alpha / Q000187:drug effects / Q000502:physiology; D014162:Transfection
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D005982:Glutathione Transferase