S 26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects.
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.
Carmona
Maria Carmen
MC
UMR 5241, CNRS-UPS, IFR 31, BP84225, 31432 Toulouse Cedex 4, France.
Louche
Katie
K
Lefebvre
Bruno
B
Pilon
Antoine
A
Hennuyer
Nathalie
N
Audinot-Bouchez
Véronique
V
Fievet
Catherine
C
Torpier
Gérard
G
Formstecher
Pierre
P
Renard
Pierre
P
Lefebvre
Philippe
P
Dacquet
Catherine
C
Staels
Bart
B
Casteilla
Louis
L
Pénicaud
Luc
L
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
D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D005982:Glutathione Transferase