Introduction: Endocannabinoids and exogenous cannabinoids are potent regulators of feeding behavior and energy metabolism. Stimulating cannabinoid receptor signaling enhances appetite, particularly for energy-dense palatable foods, and promotes energy storage. To elucidate the underlying cellular mechanisms, we investigate here the potential role of astrocytic endocannabinoid 2-arachidonoylglycerol (2-AG). Astrocytes provide metabolic support for neurons and contribute to feeding regulation but the effect of astrocytic 2-AG on feeding is unknown. Materials and Methods: We generated mice lacking the 2-AG synthesizing enzyme diacylglycerol lipase alpha (Dagla) in astrocytes (GLAST-Dagla KO) and investigated hedonic feeding behavior in male and female mice. Body weight and baseline water and food intake was characterized; additionally, the mice went through milk, saccharine, and sucrose preference tests in fed and fasted states. In female mice, the estrous cycle stages were identified and plasma levels of female sex hormones were measured. Results: We found that the effects of the inducible astrocytic Dagla deletion were sex-specific. Acute milk preference was decreased in female, but not in male mice and the effect was most evident in the estrus stage of the cycle. This prompted us to investigate sex hormone profiles, which were found to be altered in GLAST-Dagla KO females. Specifically, follicle-stimulating hormone was elevated in the estrus stage, luteinizing hormone in the proestrus, and progesterone was increased in both proestrus and estrus stages of the cycle compared with controls. Conclusions: Astrocytic Dagla regulates acute hedonic appetite for palatable food in females and not in males, possibly owing to a deregulated female sex hormone profile. It is plausible that endocannabinoid production by astrocytes at least partly contributes to the greater susceptibility to overeating in females. This finding may also be important for understanding the effects of exogenous cannabinoids on sex hormone profiles.
Keywords: 2-AG; appetite; endocannabinoids; high-fat diet; sex hormones; sex-specific effects.