Endocrine Abstracts (2006) 11 OC25

Cannabinoids increase AMP-activated protein kinase (AMPK) enzyme activity in the hypothalamus and heart via different signalling pathways – studies in CB1 knockout animals

B Kola1, M Christ-Crain1, G Wittman2, C Leontiou1, A Grossman1, C Fekete2 & M Korbonits1

1Department of Endocrinology, Barts and the London Medical School, London, United Kingdom; 2Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.

We have recently reported that 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 in accordance with the known orexigenic and adipogenic cannabinoid effects and also with their beneficial effects on the ischaemic heart. We have studied the effects of cannabinoids on AMPK activity in tissues from wild type (WT) and CB1 knockout (KO) mice to see if the CB1 receptor is involved in these effects.

Mice were injected ip. with 10 μg Δ9-tetrahydrocannabinol (THC) and their tissues collected 1 hour later. Changes in AMPK activity were detected using a kinase assay and immunoblotting for pAMPK.

THC significantly increased AMPK activity in WT animals (hypothalamus 183±41%, heart: 218±34% of control). These responses confirm our previous data in rats. In the CB1-KO animals, hypothalamic AMPK activity was not modulated by THC injection (85±16%) suggesting that these central effects are mediated by the CB1 receptor; however, we observed a significant increase in myocardial AMPK activity (303±64%) indicating that the heart effect is not mediated by the CB1 receptor.

In conclusion, (1) the stimulatory effect of cannabinoids on AMPK activity in the hypothalamus, leading to increased food intake, is mediated by the CB1 receptor, and (2) the stimulatory effect of cannabinoids on AMPK activity in the heart, which could lead to the well-described improved tissue response after ischaemia, is not mediated via the CB1 receptor. We suggest that AMPK activation plays an important role in cannabinoid effects both in the hypothalamus and in the myocardium. These data provide support for the existence of the previously suggested nonCB1-nonCB2 receptor in the heart and could lead to specifically designed cardio-specific therapies not affecting CB1 receptors and therefore devoid of central psychogenic and orexigenic effects.

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