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RESEARCH PRODUCT

Impact du système endocannabinoïdien sur la physiologie de l'obésité : effets de l'antagonisme des récepteurs CB1 sur le métabolisme glucido-lipidique de la souris obèse

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description

The endocannabinoïd system (ECS) is involved in many biological functions such as regulation of energy metabolism. Recently, several studies have shown an association between obesity and ECS overactivity. In addition, specific CB1R antagonists such as Rimonabant (SR141716) improved metabolic parameters in obese patients essentially through inactivation of central CB1R. However, peripheral CB1R inactivation could also contribute to the improvement of these parameters and it is this notion that we have studied. To this purpose, we tested the effects of SR141716 on obese mice in order to establish relationships between the ECS activity and lipid metabolism by looking more specifically to its regulation in two key tissues, the liver and the adipose tissue (AT). Obese mice previously fed with a high sucrose high fat diet were treated six weeks by SR141716 and this treatment induced weight loss associated with a normalization of plasmatic parameters and a reduction of hepatic steatosis. The major hypothesis of this study is that steatosis reversion was associated with a beneficial effect of treatment on visceral AT metabolism and that SR141716 would have direct effects on peripheral tissues. Therefore, these effects of CB1R antagonism on peripheral lipid metabolism have been studied in vitro. In this way, we first developed a model of liver explants in culture treated with SR141716. In this model, CB1R antagonism in the liver was associated with a decrease in CB1 gene expression and in certain conditions with an increased in -oxidative capacity. Finally, in order to study the impact of the ECS on adipocyte metabolism, we developed a model of cultured AT explants distinguishing visceral and subcutaneous AT. Preliminary results suggested that CB1R antagonism limits lipolysis in visceral AT. In conclusion, this work showed that peripheral CB1R are a very promising therapeutic target for treating obesity and related disorders.