Abstract
Over the years, the knowledge regarding the relevance of the cannabinoid system to the regulation of metabolism has grown steadily. A central interaction between the cannabinoid system and ghrelin has been suggested to regulate food intake. Although the stomach is the main source of ghrelin and CB1 receptor expression in the stomach has been described, little information is available regarding the possible interaction between the gastric cannabinoid and ghrelin systems in the integrated control of energy homeostasis. The main objective of the present work was to assess the functional interaction between these two systems in terms of food intake using a combination of in vivo and in vitro approaches. The present work demonstrates that the peripheral blockade of the CB1 receptor by rimonabant treatment decreased food intake but only in food-deprived animals. This anorexigenic effect is likely a consequence of decreases in gastric ghrelin secretion induced by the activation of the mTOR/S6K1 intracellular pathway in the stomach following treatment with rimonabant. In support of this supposition, animals in which the mTOR/S6K1 intracellular pathway was blocked by chronic rapamycin treatment, rimonabant had no effect on ghrelin secretion. Vagal communication may also be involved because rimonabant treatment was no longer effective when administered to animals that had undergone surgical vagotomy. In conclusion, to the best of our knowledge, the present work is the first to describe a CB1 receptor-mediated mechanism that influences gastric ghrelin secretion and food intake through the mTOR pathway.
Highlights
The stimulatory effect of Cannabis sativa on appetite has been well known for centuries [1]
Ghrelins orexigenic action was blocked by peripheral injections of rimonabant in both overnight fasted animals and satiated animals
The main findings of the present work are as follows: 1) peripheral CB1 receptors modulate food intake through a mechanism that implies gastric ghrelin regulation that requires intact vagal communication; 2) CB1 receptors are localized in the neuroendocrine cells of the stomach; and 3) Gastric CB1 receptors modulate gastric ghrelin secretion at the intracellular level through the mTOR pathway
Summary
The stimulatory effect of Cannabis sativa on appetite has been well known for centuries [1]. The characterization of the specific cannabinoid CB1 and CB2 receptors and the isolation of endogenous cannabinoids have revealed the existence of an endocannabinoid system. Knowledge about energy homeostasis regulation was boosted with the isolation of ghrelin from the stomach in 1999 [3]; and this gastric-derived peptide has been proposed to be a link between the stomach and the central nervous system. The interaction between ghrelin and the cannabinoid system has previously been proven via the demonstration of the inhibitory effect of centrally and peripheral administered rimonabant (an antagonist of the CB1 receptor) on the orexigenic and GH releasing effect of ghrelin [4,5,6]. It has been reported that both systems depend on interactions with the AMPK pathway in the hypothalamus and peripheral tissues [7,8].
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