The
AMP-activated protein kinase (AMPK) system is a key player in regulating energy balance at both the cellular and whole-body levels, placing it at centre stage in studies of
obesity, diabetes and the
metabolic syndrome. It is switched on in response to metabolic stresses such as muscle contraction or
hypoxia, and modulated by
hormones and
cytokines affecting whole-body energy balance such as
leptin,
adiponectin,
resistin,
ghrelin and
cannabinoids. Once activated, it switches on catabolic pathways that generate
adenosine triphosphate (
ATP), while switching off
ATP-consuming anabolic processes. AMPK exists as heterotrimeric complexes comprising a catalytic alpha-subunit and regulatory beta- and gamma-subunits. Binding of
AMP to the gamma-subunit, which is antagonized by high
ATP, causes activation of the
kinase by promoting phosphorylation at
threonine (Thr-172) on the alpha-subunit by the upstream
kinase LKB1, allowing the system to act as a sensor of cellular energy status. In certain cells, AMPK is activated in response to elevation of cytosolic Ca2+ via phosphorylation of Thr-172 by
calmodulin-dependent
kinase kinase-beta (
CaMKKbeta). Activation of AMPK, either in response to exercise or to pharmacological agents, has considerable potential to reverse the metabolic abnormalities associated with
type 2 diabetes and the
metabolic syndrome. Two existing classes of
antidiabetic drugs, that is,
biguanides (for example,
metformin) and the
thiazolidinediones (for example,
rosiglitazone), both act (at least in part) by activation of AMPK. Novel drugs activating AMPK may also have potential for the treatment of
obesity.