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Science 336 (6083): 918-922

Copyright © 2012 by the American Association for the Advancement of Science

The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase

Simon A. Hawley,1 Morgan D. Fullerton,2 Fiona A. Ross,1 Jonathan D. Schertzer,2 Cyrille Chevtzoff,1 Katherine J. Walker,1 Mark W. Peggie,3 Darya Zibrova,3 Kevin A. Green,1 Kirsty J. Mustard,1 Bruce E. Kemp,4 Kei Sakamoto,3,* Gregory R. Steinberg,2,4 D. Grahame Hardie1,{dagger}

Abstract: Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate–activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.

1 Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
2 Divisions of Endocrinology and Metabolism, Department of Medicine, and Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
3 Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
4 St. Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065 Australia.

* Present address: Nestlé Institute of Health Sciences Société Anonyme, Campus École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.

{dagger} To whom correspondence should be addressed: E-mail: d.g.hardie{at}

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   Abstract »    Full Text »    PDF »
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J. Wu, D. Puppala, X. Feng, M. Monetti, A. L. Lapworth, and K. F. Geoghegan (2013)
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