CB1 cannabinoid receptor expressed on astrocytes is required for feeding behaviours and leptin-mediated functions

While endocannabinoid-mediated regulations of feeding behaviours are generally attributed to neuronal expression of CB1 cannabinoid receptor (CB1), recent data suggested the participation of astrocyte-dependent mechanisms. Therefore, by generating a mouse line in which the CB1 gene was conditionally disrupted from GFAP-positive cells (GFAP-CB1-KO mice), we herein show that astroglial CB1 partially controls feeding behaviours. Thus, deletion of CB1 from GFAP-positive cells leads to a reduction of basal food intake. Because the expression of receptor for leptin (ObR), a key peripheral hormone regulating energy balance has been recently reported on astrocytes, we further examined whether cannabinoid and leptin systems could interact at astroglial level and possibly contribute to the CB1-GFAP-KO mouse phenotype. As expected, ObR was detected in primary astrocytes. However, a severe reduction of ObR expression was observed either in cultures derived from full CB1-KO mice or in WT cultures exposed to rimonabant. Accordingly, the evaluation of leptin-mediated STAT phosphorylations as well as the leptin-stimulated glycogen accumulation further indicated that CB1 deficiency abolishes leptin-mediated functions. Finally, to investigate the physiological significance of the astrocytic CB1-dependent impairment of leptin system, we injected leptin in WT and GFAP-CB1-KO mice. As expected, leptin induced significant reductions of both food intake and body weight of WT animals. However, this treatment only slightly reduces food consumption by GFAP-CB1-/- mice which however displayed a considerable reduction of body weight. Altogether, these results reveal a crucial role of astroglial CB1 receptor in feeding behaviours. Particularly, our data evidence a direct control of this receptor on leptin-mediated functions in vitro and in vivo. Furthermore, beyond the investigation of astroglial CB1 functions, this study clearly supports direct involvement of astrocytes in basal physiological processes