Figure 3.

Mechanism and Role of AMPK activation. AMP-activated protein kinase (AMPK), a serine/threonine kinase, is an energy sensor whose activity is regulated by glucose. AMPK activation, secondary to a change in the AMP/ATP ratio, activation by upstream kinases, such as CAMKK (CaMK kinase) and LKB1, or administration of metformin by direct activation of LKB1, slows metabolic reactions that consume ATP and stimulates reactions that produce ATP, thereby restoring the AMP/ATP ratio and the normal cellular energy stores. AMPK activation will in turn induce catabolic pathways, such as fatty acid oxidation by inactivating acetyl CoA carboxylase (ACC2), and will inhibit anabolic pathways, such as fatty acid synthesis, mediated by ACC1. The mTOR pathway suppresses apoptosis via its effect on the tumor suppressors p53 and p27 and inhibits autophagy by suppressing UNC-51-like kinase 1 (ULK1) and ULK2. AMPK activation downregulates the tumorigenic effects of mTOR through the TSC1/TSC2 complex, thus leading to increased apoptosis and autophagy-mediated cell death. AMPK activation also inactivates P70S6K and 4E-BP1 subsequently inhibiting protein synthesis. AMPK activation regulates the transcription factor FOXO3, which in turn increases antioxidant gene expression.