Type-1 cannabinoid (CB1) and leptin (ObR) receptors regulate metabolic and astroglial functions, but the potential links between the two systems in astrocytes were not investigated so far. Genetic and pharmacological manipulations of CB1 receptor expression and activity in cultured cortical and hypothalamic astrocytes demonstrated that cannabinoid signaling controls the levels of ObR expression. Lack of CB1 receptors also markedly impaired leptin-mediated activation of signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5) in astrocytes. In particular, CB1 deletion determined a basal overactivation of STAT5, thereby leading to the downregulation of ObR expression, and leptin failed to regulate STAT5-dependent glycogen storage in the absence of CB1 receptors. These results show that CB1 receptors directly interfere with leptin signaling and its ability to regulate glycogen storage, thereby representing a novel mechanism linking endocannabinoid and leptin signaling in the regulation of brain energy storage and neuronal functions.
Keywords: Astroglial CB1 receptors; Astroglial leptin receptor; CB1, type-1 cannabinoid receptor; Cannabinoid; Cx, cerebral cortex; FAAH, fatty acid amide hydrolase; GFAP, glial fibrillary acidic protein; Glycogen; Leptin signaling; MGL, monoacylglycerol lipase; ObR, leptin receptor; ObRb, long-isoform leptin receptor; P-STAT3, Tyr705-phosphorylated form of STAT3; P-STAT5, Tyr694-phosphorylated form of STAT5; STAT3 and 5; STAT3, transducers and activators of transcription 3; STAT5, transducers and activators of transcription 5; VMH, ventromedial hypothalamus.