AMP-activated protein kinase activators have compound and concentration-specific effects on brain metabolism

AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577 and indirectly with AICAR and metformin. We studied the resultant metabolism of [1-C-13]glucose and [1,2-C-13]acetate using NMR spectroscopy. We found distinct activator concentration-dependent effects on metabolism, which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct versus indirect activators produced distinct metabolic outcomes at both low (EC50) and higher (EC50 x 10) concentrations. Specific direct activation of beta 1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production, as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration- and mechanism-dependent impact.

Automated summary

AMP-activated protein kinase (AMPK) plays an important role in balancing anabolic and catabolic activities, and may have significant impacts on brain metabolism due to its high energy demands. Through NMR spectroscopy, we activated AMPK in guinea pig cortical tissue slices using direct and indirect activators, and found that different activator concentrations had distinct effects on metabolism. Direct activation with PF 06409577 increased Krebs cycle activity and restored pyruvate metabolism, while A769662 increased lactate and alanine production, as well as labeling of citrate and glutamine. These findings highlight the complex metabolic response to AMPK activators in the brain and emphasize the need for further research on their concentration- and mechanism-dependent impact.