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The AMPK signaling cascade in metabolic regulation: view from the chair

International Journal of Obesity volume 32, pages S3–S6 (2008)Cite this article

The AMP-activated protein kinase (AMPK) system is a key player in the regulation of cellular energy levels. By switching on catabolic pathways that generate ATP, this molecular switch triggers substrate oxidation processes during physical exercise and mediates the metabolic actions of several hormones and adipokines known to control whole-body energy balance. In this symposium, we learned about the discovery of AMPK, from the details of its complex molecular structure to its molecular mechanisms of activation by metabolic stresses, exercise and humoral factors. As AMPK is also activated by two classes of antidiabetic drugs (for example, biguanides and thiazolidinediones) it represents an attractive target for the treatment of obesity and its associated metabolic abnormalities. The potential upstream and downstream signals that may be involved in relaying AMPK's metabolic actions were also discussed by several speakers of the symposium as summarized below.

The mammalian AMPK system was discovered two decades ago by the first speaker of this session, Grahame Hardie, who initially reported that AMPK phosphorylates and inactivates key enzymes of lipid biosynthesis, that is acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase.1 Hardie showed that AMPK exists as heterotrimeric complexes consisting of catalytic α-subunits and regulatory β- and γ-subunits encoded by distinct genes. Evidence was also presented that the AMPK α-subunits are phosphorylated and activated by the tumor suppressor LKB1 kinase complex and this likely explains much of the tumor suppressor effect of AMPK activation. In addition, we also learned that in some cells AMPK activation can be induced by increases in cytoplasmic Ca2+ and consequent activation of calmodulin-dependent kinase kinase-β (CaMKKβ) (see summary of David Carling's presentation for more details on upstream AMPK kinases). Furthermore, it was proposed that AMPK can also sense some aspect of glycogen structure and provide feedback regulation on glycogen synthesis. It is thought that this might occur through an interaction of glycogen particles with the AMPK β-subunit glycogen-binding domain. Whether this interaction plays a role in the phosphorylation and inactivation of glycogen synthase by AMPK remains to be clarified. Interestingly, the AMPK β-subunits appear to form the regulatory binding sites for AMP and ATP through specific modules (termed Bateman domains) and mutations in these domains cause heart diseases associated with excessive glycogen storage.

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Acknowledgements

The author wishes to thank Phillip J White for critical reading and editing of the manuscript.

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  1. Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Québec, QC, Canada

    A Marette

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Marette, A. The AMPK signaling cascade in metabolic regulation: view from the chair. Int J Obes 32 (Suppl 4), S3–S6 (2008). https://doi.org/10.1038/ijo.2008.115

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