Tripartite mechanism by which AMPK is activated by changes in cellular energy status. Displacement of ATP by ADP and/or AMP at one or more of the sites on the AMPK-γ subunit causes a conformational change in the heterotrimeric complex that 1) promotes phosphorylation, and 2) inhibits dephosphorylation of Thr-172, causing a large (up to 100-fold) increase in kinase activity. Binding of AMP, but not ADP, causes 3) further activation of the phosphorylated kinase of up to 10-fold. The upstream kinase LKB1 appears to be constitutively active, and increased Thr-172 phosphorylation in response to energy stress does not normally occur in tumor cells lacking LKB1. However, AMPK can also be activated by Thr-172 phosphorylation catalyzed by CaMKKβ via a mechanism that requires an increase in intracellular Ca2+ but can be independent of changes in AMP and/or ADP.
Schematic diagram of the proposed new mechanism by which metformin inhibits hepatic gluconeogenesis (42). Up or down arrows next to a metabolite or enzyme show the direction the concentration or activity changes in response to metformin. Metformin (whose uptake into hepatocytes is promoted by the organic cation transporter [OCT1]) accumulates in mitochondria where it inhibits Complex 1 of the respiratory chain, lowering cytoplasmic ATP and increasing ADP and AMP. AMP activates AMPK but also inhibits adenylate cyclase, reducing effects of glucagon on cAMP and PKA and thus reducing the ability of PKA to promote gluconeogenesis by phosphorylation of PFK2 and other targets regulating transcription of gluconeogenic genes. F16BP, fructose-1,6-bisphosphate; F16BPase, fructose-1,6-bisphosphatase; F26BP, fructose-2,6-bisphosphate; G6Pase, glucose-6-phosphatase; PFK1, 6-phosphofructo-1-kinase; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.