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RESEARCH PRODUCT

Role of the peripheral endocannabinoid system in the obesity-linked metabolic disorders genesis : Involvement of adipose tissue derived endocannabinoids.

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Obesity is a pathology characterized by an excess of adipose tissue (AT) whose functions may be altered. Interestingly, strong evidence suggests that metabolic dysregulations linked to obesity is associated with an hyperactivation of the endocannabinoid system (ECS) in several organs including AT. This system, composed of cannabinoid receptors (CB1R and CB2R), their endogenous ligands (EndoCannabinoids - ECs) and their biosynthetic and degrading enzymes, is expressed both in the central nervous system and in various peripheral tissues.CB1R blockade with Rimonabant, the first antagonist marketed in 2006, has proven to be an effective therapeutic approach by reducing food intake, body mass and by significantly improving metabolic parameters. However, the associated severe centrally-mediated psychiatric disorders led to its market withdrawal 2 years later.Since then, the use of antagonists that do not cross the blood-brain barrier has demonstrated that inactivation of peripheral CB1R is sufficient to reduce the cardiometabolic risk in obese mice. Considering the central role played by AT in the etiology of obesity-associated pathologies, it appears important to clarify the existing relationship between ECS and adipocyte metabolism. In this context, these thesis objectives were to clarify the role of ECs on adipocyte lipolytic activity, to evaluate the secretory abilities of the different AT deposits and to study the impact of CB1R agonists and antagonists on adipogenesis. A last part is devoted to the characterization of the biological activity of new CB1R antagonists.First of all, studying the consequences of the ECS modulation on lipolytic activity allowed us to demonstrate that the activation of CB1R, by stimulating the PI3K/Akt signaling pathway, leads to a decrease in lipolysis. The results also suggest that AT-derived ECs could be the source of circulating ECs and be responsible for harmful exocrine effects.Studying ECs production in vitro, using visceral and subcutaneous AT explants from both obese mice and humans, confirmed the alteration of ECs secretory abilities. These preliminary results validated an original methodological approach that allows us to further explore the mechanisms of ECs production.In addition, the role of ECs on stem cells differentiation from the stroma-vascular fraction of healthy and pathological mice AT has been studied. Preliminary data are suggesting a link between adipocyte differentiation and CB1R activity.Finally, characterization studies of new CB1R antagonists have demonstrated interesting effects of the compounds JM-00266 and HR-0133 on body mass as well as on lipid and carbohydrate metabolism. Nonetheless, the optimization, development, and characterization of these new types of antagonists for therapeutic purposes is still incomplete and appears essential in the fight against obesity and obesity-associated disorders.Key words : Obesity, Endocannabinoid system, Adipose tissue, Lipid and carbohydrate metabolism