Fig. 1

Model for hierarchical activation of different subcellular pools of AMPK. Discrete pools of AMPK are activated by different intensities of stimulation: high-sensitivity (low stress) activates lysosomal-associated AMPK in response to a reduction in fructose 1,6 bisphosphate (FPB); medium-sensitivity (moderate stress) activates the cytosolic fraction of AMPK in response to a modest increase in AMP (30–60 μM); low-sensitivity (severe stress) activates mitochondrial-associated AMPK in response to a marked increase in AMP (>100 μM). Binding of LKB1 to axin is necessary for phosphorylation of AMPK on Thr172 by the high- and medium-sensitivity pathways, whereas the low-sensitivity pathway is axin independent. The different subcellular pools of AMPK phosphorylate distinct downstream targets, here exemplified by phosphorylation of either ACC1 (axin-dependent, lysosomal, and cytosolic pools) and ACC2 (axin-independent, mitochondrial pool). A potential implication of these findings is that the immediate effect of AMPK activation to low-stress conditions is inhibition of anabolic pathways (e.g., lipogenesis). Activation of catabolic pathways (e.g., fatty acid oxidation) occurs only after more severe metabolic stress. AMPK activation in the nucleus was not detected even after severe metabolic stress, and this is consistent with a previous study,⁹ which reported that AMPK activation in the nucleus required elevation of intracellular Ca²⁺. As shown here, it is possible that activation of AMPK in the nucleus is downstream of CAMKK2 signaling, which would likely be independent of axin, and could lead to changes in gene expression, mediated by phosphorylation of transcription factors