The Cannabinoid Effects of Rimonabant interact with Gherlin to Alter Food Intake

AMPK is an important mediator of both ghrelin and the endocannabinoids, and that both classes of agents have peripheral as well as central effects, and that they may interact at the cellular level. The hypothalamus plays a key role in the control of appetite and energy balance. Several compounds, including ghrelin and endocannabinoids, affect appetite at this level but also have metabolic effects in peripheral tissues.

We have previously showed1 that the stimulatory effect of ghrelin on food intake can be abolished by the cannabinoid type 1 receptor antagonist rimonabant suggesting that ghrelin and endocannabinoid systems interact.

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status: it is activated by decreases in the energy state of a cell and, once activated, switches off anabolic pathways and activates catabolic pathways. We have speculated that ghrelin and the endocannabinoids may exert both central and peripheral effects via AMPK.

Rats were injected ICV with ghrelin 1ug/rat, the endocannabinoid 2-arachydol glycerol (2AG) 50ug/rat, or vehicle, for hypothalamic experiments and with IP ghrelin 100ug/rat or tetrahydrocannabinol (THC) 2mg/kg, or vehicle, to investigate the effect of ghrelin and endocannabinoids on AMPK in peripheral tissues. AMPK activity was tested with an AMPK functional assay and with immunoblotting for AMPK.

Both ghrelin (0.42nmol ATP/min/mg) and 2AG (0.41nmol) significantly increased AMPK activity in the hypothalamus, respectively 153% and 156 % of the control (0.28nmol) showing that not only ghrelin but also the endocannabinoids may affect AMPK activity and may therefore play a role in their orexigenic effect.

Ghrelin (0.34nmol) and THC (0.53nmol) inhibited significantly AMPK in liver tissue, respectively 30% and 51% of the control (1.06nmol), while there was no change in muscle AMPK activity. Immunoblotting for phosphorylated AMPK showed similar stimulation in the hypothalamus (ghrelin 242%, 2AG 318% of control) and inhibition in the liver (ghrelin 36%, THC 65% of control), concordant with the detected changes in functional activity.

Ghrelin and endocannabinoids exercise their stimulatory feeding effects in the hypothalamus, at least in part, by activating AMPK. Ghrelin and endocannabinoids both inhibit AMPK activity in the liver while having no effect on skeletal muscle. Together with previous studies, we interpret our data to suggest that AMPK is an important mediator of both ghrelin and the endocannabinoids, and that both classes of agents have peripheral as well as central effects, and that they may interact at the cellular level.

S. A. Tucci, E. K. Rogers, M. Korbonits, and T. C. Kirkham. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br.J Pharmacol 143 (5):520-523, 2004.
ENDO 2005 ORAL SESSION: BASIC – Central Nervous System & Gut Regulatory Peptides (1:00 PM-2:30 PM)

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