Abstract
IntroductionGhrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. The cannabinoid receptor type 1 (CB1) antagonist rimonabant can block the orexigenic effect of ghrelin. In this study, we have elucidated the mechanism of the putative ghrelin-cannabinoid interaction.MethodsThe effects of ghrelin and CB1 antagonist rimonabant in wild-type mice, and the effect of ghrelin in CB1-knockout animals, were studied on food intake, hypothalamic AMPK activity and endogenous cannabinoid content. In patch-clamp electrophysiology experiments the effect of ghrelin was assessed on the synaptic inputs in parvocellular neurons of the hypothalamic paraventricular nucleus, with or without the pre-administration of a CB1 antagonist or of cannabinoid synthesis inhibitors.Results and ConclusionsGhrelin did not induce an orexigenic effect in CB1-knockout mice. Correspondingly, both the genetic lack of CB1 and the pharmacological blockade of CB1 inhibited the effect of ghrelin on AMPK activity. Ghrelin increased the endocannabinoid content of the hypothalamus in wild-type mice and this effect was abolished by rimonabant pre-treatment, while no effect was observed in CB1-KO animals. Electrophysiology studies showed that ghrelin can inhibit the excitatory inputs on the parvocellular neurons of the paraventricular nucleus, and that this effect is abolished by administration of a CB1 antagonist or an inhibitor of the DAG lipase, the enzyme responsible for 2-AG synthesis. The effect is also lost in the presence of BAPTA, an intracellular calcium chelator, which inhibits endocannabinoid synthesis in the recorded parvocellular neuron and therefore blocks the retrograde signaling exerted by endocannabinoids. In summary, an intact cannabinoid signaling pathway is necessary for the stimulatory effects of ghrelin on AMPK activity and food intake, and for the inhibitory effect of ghrelin on paraventricular neurons.
Highlights
Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation
Ghrelin had no effect on food intake in the cannabinoid receptor type 1 (CB1)-KO mice, suggesting that the effect of ghrelin on appetite is dependent on CB1
In this study we have shown that the effect of ghrelin on the mechanism of appetite regulation is CB1-dependent: (i) ghrelin and cannabinoids increase hypothalamic AMPK activity and an intact CB1 receptor is mandatory for these effects; (ii) ghrelin increases the cannabinoid content of the hypothalamus and interestingly CB1 is involved in this effect; (iii) ghrelin inhibits excitatory synaptic input in the PVN, an effect which can be abolished by a CB1 antagonist as well as via inhibition of cannabinoid synthesis with the use of BAPTA, an intracellular calcium chelator, and with the use of THL, an inhibitor of the 2AG synthesizing enzyme DAG lipase; and (iv) ghrelin stimulates appetite and an intact CB1 receptor is necessary for this effect
Summary
Ghrelin and cannabinoids stimulate appetite, this effect possibly being mediated by the activation of hypothalamic AMP-activated protein kinase (AMPK), a key enzyme in appetite and metabolism regulation. Ghrelin is a brain-gut peptide that stimulates appetite and has direct effects on the regulation of energy balance in the periphery [1]. It promotes appetite via effects in the hypothalamic arcuate and paraventricular (PVN) nuclei, both known to be involved in appetite regulation [2]. Hypothalamic AMPK is a mediator of several appetite-regulating hormones; it is inhibited by leptin and a-melanocyte stimulating hormone and activated by ghrelin and cannabinoids [7,8,10]. CB1 is mainly localized to presynaptic axon terminals and activated by endocannabinoids synthesized and released by the postsynaptic neurons, a phenomenon otherwise known as retrograde signaling [12]
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