Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice.
OBJECTIVE
Fibrates and thiazolidinediones are commonly used for the treatment of dyslipidemia and type 2 diabetes, respectively. The aim of this study was to investigate the effects on body weight as well as on glucose and lipid homeostasis of ligands for PPARalpha and PPARgamma, Fenofibrate and Rosiglitazone, alone or in association.


METHODS
Ob/ob mice were divided into four groups: control, and mice daily injected (intraperitoneally), either with 10 mg/kg Rosiglitazone, 100 mg/kg Fenofibrate or both molecules. Body weight and food intake were monitored daily. After 13 days of treatment, mice were killed, and blood samples were collected for posterior metabolite quantification. The liver and adipose tissues were dissected and weighed.


RESULTS
Body weight was significantly reduced or increased by Fenofibrate and Rosiglitazone, respectively. The effect of Rosiglitazone was prevented by coadministration of Fenofibrate. This was accompanied by a normalization of the daily food efficiency. Compared to those treated with Rosiglitazone, animals treated with Fenofibrate alone or in combination presented a decreased white adipose tissue mass. Fenofibrate or Rosiglitazone alone significantly reduced the levels of plasma lipid parameters. Surprisingly, Fenofibrate also decreased blood glucose levels in ob/ob mice, despite having no effect on insulin levels. By contrast, both glucose and insulin levels were decreased by Rosiglitazone treatment. Coadministration of both drugs improved all parameters as with Rosiglitazone. Fenofibrate restored almost normal hepatocyte morphology and significantly reduced the triglyceride content of the liver. This was accompanied by an increase in fatty acid oxidation in the liver in all groups receiving Fenofibrate.


CONCLUSIONS
These biological effects suggest that combined therapy with a PPARalpha and a PPARgamma ligand is more effective in ameliorating, specifically, lipid homeostasis than in activating any of this receptor separately. Furthermore, Fenofibrate prevents one of the most undesirable effects of Rosiglitazone, namely increased adiposity and body weight gain.
Carmona
M C
MC
UMR 5018 CNRS-UPS, IFR 31, CHU Rangueil, Toulouse, France.
Louche
K
K
Nibbelink
M
M
Prunet
B
B
Bross
A
A
Desbazeille
M
M
Dacquet
C
C
Renard
P
P
Casteilla
L
L
Pénicaud
L
L
D000818:Animals; D001823:Body Composition / Q000187:drug effects; D003864:Depression, Chemical; D004359:Drug Therapy, Combination; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000378:metabolism / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000627:therapeutic use*; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
D005227:Fatty Acids; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D011345:Fenofibrate