Juleen R. Zierath, Karolinska Institutet, Department of Molecular Medicine and Surgery, Section of Integrative Physiology, von Eulers väg 4, 4th floor, S-171 77 Stockholm, Sweden, Phone: +46 8 524 875 80, Fax: +46 8 33 54 36, E-mail: Juleen.Zierath@ki.se

AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. An important feature of AMPK as a putative signal transducer for metabolic and gene regulatory adaptations is its capacity to monitor and response to the cellular energy status. In general, activation of AMPK triggers catabolic pathways that produce ATP, while turning off anabolic pathways that consume ATP, to maintain cellular energy stores (1, 2). AMPK is a heterotrimeric complex composed of a catalytic α, and regulatory β and γ subunits (1-3). Each α and β subunits are encoded by distinctive genes (α1, α2 and β1, β2), whereas the γ subunit is encoded by three genes (γ1, γ2 and γ3). AMPK is activated by an increase in the ratio of AMP:ATP within the cell, and therefore it functions as an efficient metabolic sensor. Binding of AMP to the g -subunit activates AMPK allosterically, and promotes the phosphorylation of threonine residue (Thr-172) within the activation domain of α subunit by an upstream kinase, the tumor suppressor LKB1 (1, 2). This phosphorylation is further sustained by an inhibitory effect of AMP on dephosphorylation at Thr-172 by protein phosphatases (4). The marked sensitivity of AMPK to the AMP:ATP ratio is also conferred by an antagonistic effect of high ATP on the AMP-mediated activation of AMPK (2). Calmodulin-dependent protein kinase kinase (CaMKK) is an additional upstream kinase of AMPK (5-7). Activation of AMPK by CaMKK is stimulated by an increase in intracellular calcium ions, which appears to be independent of changes in AMP:ATP ratio (5).

AMPK is activated by a wide array of metabolic stresses including exercise, hypoxia, ischemia, oxidative and hyperosmotic stresses (1, 2, 8-11). AMPK plays a central role in the regulation of whole body glucose homeostasis (10, 11). Activation of AMPK in skeletal muscle, liver and adipose tissue results in a favorable metabolic milieu for the prevention or treatment of non-insulin-dependent (Type 2) diabetes mellitus, by potentially decreased circulating glucose, reducing plasma lipid and ectopic fat accumulation, as well as enhancing insulin sensitivity and promoting mitochondrial biogenesis. AMPK also regulates food intake by responding to hormonal and nutrient signals in the hypothalamus (12). Alterations in glucose and energy homeostasis caused by undefined genetic factors, as well as by overeating and a sedentary lifestyle, lead to obesity and Type 2 diabetes. Interestingly, metformin (13) and thiazolidinediones (14), two widely prescribed drugs for the treatment of Type 2 diabetes increase AMPK activity and enhance insulin sensitivity, underscoring the potential role of the AMPK pathway in the treatment of metabolic disease (15).

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