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First published online on April 27, 2006.
 Copyright © 2006 by The Physiological Society
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Received March 6, 2006
Revised March 24, 2006
Accepted after revision April 13, 2006

AMP-activated protein kinase - development of the energy sensor concept

David Grahame Hardie1*, Simon A. Hawley1, and John W Scott1

1 University of Dundee

* To whom correspondence should be addressed. E-mail: d.g.hardie{at}dundee.ac.uk.

The LKB1 -> AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP:ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory {gamma} subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while decreasing food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving calcium/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used anti-diabetic drug, metformin.


Key words: Energy • Metabolic regulation • Protein kinase




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