Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase

Blerina Kola,Erika Hubina,Sonia A Tucci,Tim C Kirkham,Edwin A Garcia,Sharon E Mitchell,Lynda M Williams,Simon A Hawley,D Grahame Hardie,Ashley B Grossman,Márta Korbonits

doi:10.1074/jbc.c500175200

Abstract

Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor gamma agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.

Highlights

Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level
In the current study using a functional AMPK assay we observed that in whole hypothalamus total AMPK activity increased to 153 Ϯ 8% of control after central 2-AG injection and to 156 Ϯ 26% after i.c.v. ghrelin injection (Fig. 1A)
Cannabinoids were found to stimulate AMPK activity in the hypothalamus after both central and peripheral administration. We propose that this effect of cannabinoids on AMPK represents an important pathway which mediates their orexigenic effect

Summary

Introduction

Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level Both have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. It is activated by any stress that depletes cellular ATP, with a concomitant rise in AMP, causing increased phosphorylation of the ␣ subunit on Thr-172 by the upstream kinase, the tumor suppressor serine/ threonine kinase LKB1 [18, 19] Both metformin and peroxisome proliferator-activated receptor ␥ agonists have been shown to activate AMPK, and it is suggested that this effect is important in the anti-diabetic action of these compounds. We report a stimulatory effect of both cannabinoids and ghrelin on AMPK in the hypothalamus and in heart muscle, together with a contrasting inhibitory effect in liver and adipose tissue, but no detectable effect on skeletal muscle

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Results

Conclusion