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J. Biol. Chem., Vol. 275, Issue 22, 16638-16642, June 2, 2000
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From Fibrates and glitazones are two classes of drugs
currently used in the treatment of dyslipidemia and insulin resistance
(IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR)
Peroxisome Proliferator-activated Receptor
Activators Improve
Insulin Sensitivity and Reduce Adiposity*
,
,
Unité 465, INSERM, Institut
Biomédical des Cordeliers, F-75006 Paris, France,
§ Unité 325, INSERM, Département
d'Athérosclérose, Institut Pasteur de Lille, F-59019
Lille, France, the Faculté de Pharmacie, Université de
Lille II, F-59006 Lille, France, the ¶ Department of Clinical
Biology, Division of Biochemistry, University of Bergen, Haukeland
Hospital, N-5021 Bergen, Norway, Sanofi Recherche, F-31036
Toulouse, France, and ** Glaxo Wellcome Research and Development,
Research Triangle Park, North Carolina 27709
subtype, fibrates exert their lipid-lowering activity via PPAR
.
To determine whether PPAR activators also improve insulin
sensitivity, we measured the capacity of three PPAR-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in
two rodent models of high fat diet-induced (C57BL/6 mice) or genetic
(obese Zucker rats) IR. At doses yielding serum concentrations shown to
activate selectively PPAR, these compounds markedly lowered
hyperinsulinemia and, when present, hyperglycemia in both animal
models. This effect relied on the improvement of insulin action on
glucose utilization, as indicated by a lower insulin peak in response
to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker
rats. In addition, fenofibrate treatment prevented high fat
diet-induced increase of body weight and adipose tissue mass without
influencing caloric intake. The specificity for PPAR activation
in vivo was demonstrated by marked alterations in the expression of PPAR target genes, whereas PPAR target gene
mRNA levels did not change in treated animals. These results
indicate that compounds with a selective PPAR activation profile
reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.
*
This work was supported by grants from the Région
Nord-Pas de Calais, Sanofi Winthrop, INSERM, and Institut Pasteur de
Lille.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: U.325 INSERM,
Dépt. d'Athérosclérose, Inst. Pasteur de Lille, 1 Rue Calmette, 59019 Lille, France. Tel.: 33-3-20-87-73-88; Fax:
33-3-20-87-73-60; E-mail: bart.staels@pasteur-lille.fr.
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