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J. Biol. Chem., Vol. 280, Issue 26, 25196-25201, July 1, 2005

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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, and Márta Korbonits||||

From the Department of Endocrinology, William Harvey Research Institute, Barts and the London Medical School, London EC1M 6BQ, United Kingdom, the Department of Internal Medicine, University of Ancona, 60100 Ancona, Italy, the ^||Department of Psychology, University of Liverpool, Liverpool, L69 7ZA, United Kingdom, the Rowett Research Institute, Aberdeen, AB21 9SB, United Kingdom, and the Division of Molecular Physiology, University of Dundee, Dundee DD1 5EH, United Kingdom

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 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.

Received for publication, April 20, 2005 , and in revised form, May 13, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by The Jules Thorn Trust.

^** Supported by the UK Biotechnology and Biological Sciences Research Council.

^*** Supported by Diabetes UK.

^¶¶ These authors were supported by the Wellcome Trust and by a contract for an Integrated Project (LSHM-CT-2004-005272) from the European Commission.

^|||| Supported by the UK Medical Research Council. To whom correspondence should be addressed: Dept. of Endocrinology, Rm. 114C, John Vane Science Centre, Barts and the London Medical School, Charterhouse Square, London EC1M 6BQ, UK. Tel.: 44-20-7882-6238; Fax: 44-20-7882-6197; E-mail: m.korbonits{at}qmul.ac.uk.

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