AMP-activated protein kinase in Sickness and Health – From Molecule to Man

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This issue of Acta Physiologica contains review articles from a group of invited speakers at the 5th International Meeting on AMPK, entitled AMPK in Sickness and Health – From Molecule to Man which was held in Snekkersten, Denmark, 10–15 August 2008. Since the first AMPK meeting held in Boston in 2000, an international meeting has been held every two years, once in the UK, once in Australia and once more in the USA. These meetings have brought forward new insights into AMPK-related cellular signalling, cellular responses and whole-body effects and constituted important forums for debates regarding the possible involvement of AMPK in various diseases and for AMPK as a potential therapeutic target for these diseases.

To give it its full name, AMP-activated protein kinase is a central regulator of cellular and whole-body energy homeostasis coordinating anabolic and catabolic pathways to balance nutrient supply with energy demand. At the cellular level this is mainly achieved by phosphorylation of key enzymes in major subdivisions of metabolism involving fat, protein and carbohydrate. At the whole-body level, AMPK plays a role in regulating food intake and body weight. In addition, AMPK is regulated by a variety of hormones including leptin, adiponectin and ghrelin, and the importance of these effects is discussed in several reviews in this series. As a consequence of these observations, AMPK has emerged as a promising target for various metabolic diseases such as obesity, insulin resistance and cardiovascular diseases. Therefore, elucidating the structural and molecular regulation of AMPK has become increasingly important in the search for pharmacological activators of AMPK. Recently, several reports have described the crystal structure of fragments of AMPK from different species, and although we still await the successful crystallization of the whole enzyme, the insight into the regulation of AMPK has been greatly facilitated by these observations as discussed in several reviews in this series. In fact, significant progress has been made in the discovery of novel and direct activators of AMPK. The observation that some of these agents display AMPK isoform specificity has opened the door to the challenging future of developing isoform- and tissue-selective AMPK activators. Specificity of agents targeting AMPK may create treatment regimes avoiding secondary undesirable effects, such as cardiac glycogen loading.

By regulating cell proliferation/growth, apoptosis and autophagy in addition to cellular and whole-body metabolism, AMPK is likely to be a fundamental factor in normal growth as well as in suppression of tumorigenesis, unravelling an exciting potential of using AMPK activators in anti-cancer treatments. Supporting this idea is already published data showing that patients with diabetes who are prescribed metformin have lower rates of cancer than those who are not treated with metformin.

Various upstream kinases in the AMPK cascade have been identified in different cell types and tissues. These upstream kinases respond to different stimuli, including increases in cellular calcium (mediated by calcium/calmodulin-dependent protein kinase kinase β) and transforming growth factor β (mediated by TAK1), or are thought to be constitutively active (as is the case for LKB1). It appears now that the action of these upstream kinases is independent of AMP, whereas the action of the protein phosphatase dephosphorylating AMPK is decreased by AMP, favouring accumulation of the phosphorylated, activated form of AMPK. Yet, AMPK is not ‘alone’– there are 12 AMPK-related kinases regulated by LKB1 and some of these, but not all, may also be regulated by other upstream kinases. Research delineating the role of these AMPK-related kinases is in its infancy and there remain many unanswered questions regarding their physiological function and regulation.

Exercise is at present the most powerful physiological activator of AMPK known. Although human data have so far not been confirmatory, rodent models have indicated that exercise may initiate AMPK activation in tissues other than the exercising muscle, such as liver and fat. Many of the effects of AMPK activation are also seen in response to exercise training and it is hypothesized that in many circumstances a causal relationship exists between the beneficial health effects of physical activity vs. the adverse effects of inactivity and the activation or lack of activation of AMPK. The observation that AMPK targets AS160 as does insulin signalling may underlie the finding that exercise promotes insulin action, and thus may be one way by which exercise improves insulin sensitivity and thus reduces the risk of insulin resistance.

On behalf of the scientific meeting committee it is our hope that the readers of Acta Physiologica will take pleasure in these review articles that elegantly represent many of the current topics related to AMPK.

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