Akt Activity Negatively Regulates Phosphorylation of AMP-activated Protein Kinase in the Heart

• Published in: The Journal of biological chemistry Vol. 278; no. 41; pp. 39422 - 39427
• Main Authors: Kovacic, Suzanne, Soltys, Carrie-Lynn M., Barr, Amy J., Shiojima, Ichiro, Walsh, Kenneth, Dyck, Jason R.B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-10-2003; American Society for Biochemistry and Molecular Biology
• Subjects: Adenovirus; AMP-Activated Protein Kinases; Animals; Cells, Cultured; Glucose - metabolism; In Vitro Techniques; Insulin - metabolism; Insulin - pharmacology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Perfusion; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M305371200

In the heart, insulin stimulates a variety of kinase cascades and controls glucose utilization. Because insulin is able to activate Akt and inactivate AMP-activated protein kinase (AMPK) in the heart, we hypothesized that Akt can regulate the activity of AMPK. To address the potential existence of this novel signaling pathway, we used a number of experimental protocols to activate Akt in cardiac myocytes and monitored the activation status of AMPK. Mouse hearts perfused in the presence of insulin demonstrated accelerated glycolysis and glucose oxidation rates as compared with non-insulin-perfused hearts. In addition, insulin caused an increase in Akt phosphorylation and a decrease in AMPK phosphorylation at its major regulatory site (threonine 172 of the α catalytic subunit). Transgenic mice overexpressing a constitutively active mutant form of Akt1 displayed decreased phosphorylation of cardiac α-AMPK. Isolated neonatal cardiac myocytes infected with an adenovirus expressing constitutively active mutant forms of either Akt1 or Akt2 also suppressed AMPK phosphorylation. However, Akt-dependent depression of α-AMPK phosphorylation could be overcome in the presence of the AMPK activator, metformin, suggesting that an override mechanism exists that can restore AMPK activity. Taken together, this study suggests that there is cross-talk between the AMPK and Akt pathways and that Akt activation can lead to decreased AMPK activity. In addition, our data suggest that the ability of insulin to inhibit AMPK may be controlled via an Akt-mediated mechanism.