Endocrine Abstracts (2006) 11 P383

Direct effect of cannabinoids and ghrelin on liver and adipose cell metabolism via the AMP-activated protein kinase (AMPK) enzyme

P Dalino, D Aguilar, AM Isidori, E Hubina, EA Garcia, B Kola, AB Grossman & M Korbonits

Department of Endocrinology, Barts and the London Medical School, London, United Kingdom.

Cannabinoids and ghrelin exert hypothalamic orexigenic effects and independent peripheral effects have also been reported. We have recently reported that ghrelin and cannabinoids can stimulate hypothalamic and heart AMPK activity, and can inhibit liver and adipose tissue AMPK activity, in rats (Kola et al., JBC, 2005). These data are concordant with the known orexigenic, adipogenic and diabetogenic effects of these compounds as well as with their beneficial effects on the ischaemic heart. However, it is not known whether the in vivo observations on metabolic tissues such as liver and fat tissue are direct effects; therefore we have now studied liver and adipose cell lines.

Rat hepatoma cell line H4 and mouse 3T3 adipose cells were treated with ghrelin 100nM (G) and with the endocannabinoid anandamide 10μM (A). Changes in AMPK activity were detected using a kinase assay, while activated AMPK content was assessed by immunoblotting.

Liver cells showed an inhibition in AMPK activity (G: 74±12%, A: 41±23% of control, P<0.005 and P<0.001 respectively) and a decrease in pAMPK content (G: 63±14%, A: 56±1%, P<0.01 for both). Adipose cells also showed inhibition of AMPK activity (G: 42±3%, A: 18±10% of control, P<0.01 for both).

In conclusion, we have shown that cannabinoids and ghrelin have a direct effect on liver and adipose cells to modulate cell metabolism via the AMPK enzyme. The fact that the liver cell line lacks expression of GHS-R1A implies that ghrelin effects occur via an alternative receptor in the liver. We are currently performing CB1 knockout animal studies to identify if this receptor is involved in the cannabinoid effect. Our data could provide a mechanism for earlier unexplained observations in various cell-based and in vivo experiments, including knockout models, regarding the direct peripheral effects of cannabinoids and ghrelin.

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