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Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice
M C Carmona1, K Louche, M Nibbelink
1UMR 5018 CNRS-UPS, IFR 31, CHU Rangueil, Toulouse, France.
Aims/Hypothesis:
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.
Conclusion/Interpretation:
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.
Insights
Fenofibrate reduced body weight and improved lipid and glucose levels in mice, while Rosiglitazone increased weight. Combination therapy with Fenofibrate and Rosiglitazone offered the most benefits for metabolic homeostasis.
Area of Science:
- Pharmacology and Endocrinology
- Metabolic Diseases Research
Background:
- Fibrates (PPARα ligands) and thiazolidinediones (PPARγ ligands) are established treatments for dyslipidemia and type 2 diabetes.
- Investigating combined effects on metabolic parameters is crucial for optimizing therapeutic strategies.
Purpose of the Study:
- To evaluate the impact of Fenofibrate (PPARα agonist) and Rosiglitazone (PPARγ agonist), alone and in combination, on body weight, glucose, and lipid homeostasis.
- To determine if Fenofibrate can mitigate adverse effects of Rosiglitazone.
Main Methods:
- Ob/ob mice were treated with Fenofibrate, Rosiglitazone, or both, alongside a control group.
- Daily monitoring of body weight and food intake, with tissue and blood analysis post-treatment.
Main Results:
- Fenofibrate decreased body weight and liver triglycerides, increasing fatty acid oxidation; Rosiglitazone increased body weight and adiposity.
- Combination therapy improved lipid and glucose parameters, with Fenofibrate preventing Rosiglitazone-induced weight gain.
- Fenofibrate alone normalized hepatocyte morphology and reduced adipose tissue mass.
Conclusions:
- Combined PPARα and PPARγ ligand therapy is superior to monotherapy for improving lipid homeostasis.
- Fenofibrate effectively counteracts the undesirable weight gain associated with Rosiglitazone treatment.
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