Maintaining Energy Balance in Health and Disease: Role of the AMP-Activated Protein Kinase

  • John W. Scott
Part of the Protein Reviews book series (PRON, volume 13)


Maintaining a steady balance between energy production and consumption is a cornerstone of all living cells. Failure to maintain this balance affects most, if not all, cellular activities as these processes are normally tightly coupled to the energy status of the cell. It is beginning to emerge that human diseases such as obesity, Type 2 diabetes, and even certain types of cancer may be linked to underlying defects in the regulation of energy balance. Since the evolution of eukaryotes, the AMP-activated protein kinase (AMPK) system has played a pivotal role in maintaining energy homeostasis by regulating the enzymes that control flux through virtually every branch of metabolism. AMPK functions primarily as a fuel gauge monitoring the ratio of AMP to ATP, which can be regarded as a molecular read-out of cellular energy status. It becomes activated when energy utilisation overtakes energy production, and serves to rectify this imbalance by upregulating ATP-producing pathways while switching off ATP-consuming pathways such as lipid, carbohydrate and protein biosynthesis. In addition to regulating energy balance at the cellular level, AMPK is also a central regulator of whole-body energy homeostasis, integrating a variety of hormonal and nutritional signals in the central nervous system and periphery to control feeding behaviour and body weight. Increasing our understanding of the regulation and physiological roles of AMPK promises to open new avenues for the treatment of a whole range of debilitating human diseases.


Fatty Acid Oxidation Mitochondrial Biogenesis Glycogen Phosphorylase Hormone Sensitive Lipase Upstream Kinase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



AMP-activated protein kinase


Acetyl CoA carboxylase


Adenosine 5’-monophosphate


Adenosine 5’-triphosphate


Ca2+/calmodulin dependent protein kinase kinase


Cystathionine-β-synthase domain


Carbohydrate-binding module



I would like to thank Prof Bruce Kemp for mentoring and helpful discussions. This work was funded by the Australian Research Council and the National Health and Medical Research Council.


  1. Abu-Elheiga, L., Jayakumar, A., Baldini, A., et al. (1995). Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms. Proc. Natl. Acad. Sci. USA 92:4011–4015.PubMedCrossRefGoogle Scholar
  2. Abu-Elheiga, L., Brinkley, W.R., Zhong, L., et al. (2000). The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl. Acad. Sci. USA 97:1444–1449.PubMedCrossRefGoogle Scholar
  3. Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A., et al. (2001). Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291:2613–2616.PubMedCrossRefGoogle Scholar
  4. Adams, J., Chen, Z.P., Van Denderen, et al. (2004). Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci. 13:155–165.PubMedCrossRefGoogle Scholar
  5. Akimoto, T., Pohnert, S.C., Li, P., Zhang, M., et al. (2005). Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J. Biol. Chem. 280:19587–19593.PubMedCrossRefGoogle Scholar
  6. Akman, H.O., Sampayo, J.N., Ross, F.A., et al. (2007). Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2-subunit of AMP-activated protein kinase. Pediatr. Res. 62:499–504.PubMedCrossRefGoogle Scholar
  7. Anderson, K.A., Ribar, T.J., Lin, F., et al. (2008). Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7:377–388.PubMedCrossRefGoogle Scholar
  8. Andersson, U., Filipsson, K., Abbott, C.R., et al. (2004). AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279:12005–12008.PubMedCrossRefGoogle Scholar
  9. Andreelli, F., Foretz, M., Knauf, C., et al. (2006). Liver adenosine monophosphate-activated kinase-alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 147:2432–2441.PubMedCrossRefGoogle Scholar
  10. Anthonsen, M.W., Ronnstrand, L., Wernstedt, C., et al. (1998). Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J. Biol. Chem. 273:215–221.PubMedCrossRefGoogle Scholar
  11. Arad, M., Benson, D.W., Perez-Atayde, et al. (2002). Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109:357–362.PubMedGoogle Scholar
  12. Aschenbach, W.G., Hirshman, M.F., Fujii, N., et al. (2002). Effect of AICAR treatment on glycogen metabolism in skeletal muscle. Diabetes 51:567–573.PubMedCrossRefGoogle Scholar
  13. Baas, A.F., Kuipers, J., van der Wel, N.N., et al. (2004). Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116:457–466.PubMedCrossRefGoogle Scholar
  14. Barnes, B.R., Marklund, S., Steiler, T.L., et al. (2004). The 5’-AMP-activated protein kinase gamma3 isoform has a key role in carbohydrate and lipid metabolism in glycolytic skeletal muscle. J. Biol. Chem. 279:38441–38447.PubMedCrossRefGoogle Scholar
  15. Bateman, A. (1997). The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem. Sci. 22:12–13.PubMedCrossRefGoogle Scholar
  16. Baur, J.A., Pearson, K.J., Price, N.L., et al. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342.PubMedCrossRefGoogle Scholar
  17. Beg, Z.H., Stonik, J.A., Brewer, H.B. Jr. (1978). 3-Hydroxy-3-methylglutaryl coenzyme A reductase: regulation of enzymatic activity by phosphorylation and dephosphorylation. Proc. Natl. Acad. Sci. USA 75:3678–3682.PubMedCrossRefGoogle Scholar
  18. Bergeron, R., Previs, S.F., Cline, G.W., et al. (2001a). Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50:1076–1082.PubMedCrossRefGoogle Scholar
  19. Bergeron, R., Ren, J.M., Cadman, K.S., et al. (2001b). Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am. J. Physiol. Endocrinol. Metab. 281:E1340–1346.PubMedGoogle Scholar
  20. Boudeau, J., Baas, A.F., Deak, M., et al. (2003). MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm. EMBO J. 22:5102–5114.PubMedCrossRefGoogle Scholar
  21. Brabant, G., Muller, G., Horn, R., et al. (2005). Hepatic leptin signaling in obesity. FASEB J. 19:1048–1050.PubMedGoogle Scholar
  22. Brunmair, B., Staniek, K., Gras, F., et al. (2004). Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53:1052–1059.PubMedCrossRefGoogle Scholar
  23. Budanov, A.V. and Karin, M. (2008). p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134:451–460.PubMedCrossRefGoogle Scholar
  24. Bulkley, B.H., and Hutchins, G.M. (1978). Pompe’s disease presenting as hypertrophic myocardiopathy with Wolff-Parkinson-White syndrome. Am. Heart. J. 96:246–252.PubMedCrossRefGoogle Scholar
  25. Burwinkel, B., Scott, J.W., Buhrer, C., et al. (2005). Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am. J. Hum. Genet. 76:1034–1049.PubMedCrossRefGoogle Scholar
  26. Carling, D. and Hardie, D.G. (1989). The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. Biochim. Biophys. Acta 1012:81–86.PubMedCrossRefGoogle Scholar
  27. Carling, D., Clarke, P.R., Zammit, V.A., et al. (1989). Purification and characterization of the AMP-activated protein kinase. Copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur. J. Biochem. 186:129–136.PubMedCrossRefGoogle Scholar
  28. Chavez, J.A., Roach, W.G., Keller, S.R., et al. (2008). Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J. Biol. Chem. 283:9187–9195.PubMedCrossRefGoogle Scholar
  29. Chen, H., Charlat, O., Tartaglia, L.A., et al. (1996). Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491–495.PubMedCrossRefGoogle Scholar
  30. Chen, Z.P., Stephens, T.J., Murthy, S., et al. (2003). Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52:2205–2212.PubMedCrossRefGoogle Scholar
  31. Chen, S., Murphy, J., Toth, R., et al. (2008). Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem. J. 409:449–459.PubMedCrossRefGoogle Scholar
  32. Civitarese, A.E., Ukropcova, B., Carling, S., et al. (2006). Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab. 4:75–87.PubMedCrossRefGoogle Scholar
  33. Clarke, P.R. and Hardie, D.G. (1990). Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J. 9:2439–2446.PubMedGoogle Scholar
  34. Clarke, C.F., Edwards, P.A., Lan, S.F., et al. (1983). Regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase mRNA levels in rat liver. Proc. Natl. Acad. Sci. USA 80:3305–3308.PubMedCrossRefGoogle Scholar
  35. Cool, B., Zinker, B., Chiou, W., et al. (2006). Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3:403–416.PubMedCrossRefGoogle Scholar
  36. Corradetti, M.N., Inoki, K., Bardeesy, N., et al. (2004). Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 18:1533–1538.PubMedCrossRefGoogle Scholar
  37. Corton, J.M., Gillespie, J.G., Hawley, S.A., et al. (1995). 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. 229:558–565.PubMedCrossRefGoogle Scholar
  38. Crute, B.E., Seefeld, K., Gamble, J., et al. (1998). Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J. Biol. Chem. 273:35347–35354.PubMedCrossRefGoogle Scholar
  39. da Silva Xavier, G., Leclerc, I., Salt, I.P., et al. (2000). Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression. Proc. Natl. Acad. Sci. USA 97:4023–4028.PubMedCrossRefGoogle Scholar
  40. Davies, S.P., Helps, N.R., Cohen, P.T., et al. (1995). 5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett. 377:421–425.PubMedCrossRefGoogle Scholar
  41. Dixon, R., Gourzis, J., McDermott, D., et al. (1991). AICA-riboside: safety, tolerance, and pharmacokinetics of a novel adenosine-regulating agent. J. Clin. Pharmacol. 31:342–347.PubMedGoogle Scholar
  42. Dowling, R.J., Zakikhani, M., Fantus, I.G., et al. (2007). Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67:10804–10812.PubMedCrossRefGoogle Scholar
  43. Dyck, J.R., Kudo, N., Barr, A.J., et al. (1999). Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5’-AMP activated protein kinase. Eur. J. Biochem. 262:184–190.PubMedCrossRefGoogle Scholar
  44. Dyck, J.R., Cheng, J.F., Stanley, W.C., et al. (2004). Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ. Res. 94:e78–84.PubMedCrossRefGoogle Scholar
  45. Dzamko, N., Schertzer, J.D., Ryall, J.G., et al. (2008). AMPK-independent pathways regulate skeletal muscle fatty acid oxidation. J. Physiol. 586:5819–5831.PubMedCrossRefGoogle Scholar
  46. Evans, J.M., Donnelly, L.A., Emslie-Smith, A.M., et al. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305.PubMedCrossRefGoogle Scholar
  47. Fogarty, S. and Hardie, D.G. (2009). C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest. J. Biol. Chem. 284:77–84.PubMedCrossRefGoogle Scholar
  48. Foretz, M., Carling, D., Guichard, C., et al. (1998). AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J. Biol. Chem. 273:14767–14771.PubMedCrossRefGoogle Scholar
  49. Fox, C.J., Hammerman, P.S., Thompson, C.B. (2005). Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5:844–852.PubMedCrossRefGoogle Scholar
  50. Fujii, N., Hayashi, T., Hirshman, M.F., et al. (2000). Exercise induces isoform-specific increase in 5’AMP-activated protein kinase activity in human skeletal muscle. Biochem. Biophys. Res. Commun. 273:1150–1155.PubMedCrossRefGoogle Scholar
  51. Fujii, N., Seifert, M.M., Kane, E.M., et al. (2007). Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle -insight from analysis of a transgenic mouse model. Diabetes Res. Clin. Pract. 77 Suppl 1:S92–S98.CrossRefGoogle Scholar
  52. Gao, S., Kinzig, K.P., Aja, S., et al. (2007). Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl. Acad. Sci. USA 104:17358–17363.PubMedCrossRefGoogle Scholar
  53. Garcia-Roves, P.M., Osler, M.E., Holmstrom, M.H., et al. (2008). Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283:35724–35734.PubMedCrossRefGoogle Scholar
  54. Garton, A.J. and Yeaman, S.J. (1990). Identification and role of the basal phosphorylation site on hormone-sensitive lipase. Eur. J. Biochem. 191:245–250.PubMedCrossRefGoogle Scholar
  55. Garton, A.J., Campbell, D.G., Carling, D., et al. (1989). Phosphorylation of bovine hormone-sensitive lipase by the AMP-activated protein kinase. A possible antilipolytic mechanism. Eur. J. Biochem. 179:249–254.PubMedCrossRefGoogle Scholar
  56. Geraghty, K.M., Chen, S., Harthill, J.E., et al. (2007). Regulation of multisite phosphorylation and 14-3-3 binding of AS160 in response to IGF-1, EGF, PMA and AICAR. Biochem. J. 407:231–241.PubMedCrossRefGoogle Scholar
  57. Ghilardi, N., Ziegler, S., Wiestner, A., et al. (1996). Defective STAT signaling by the leptin receptor in diabetic mice. Proc. Natl. Acad. Sci. USA 93:6231–6235.PubMedCrossRefGoogle Scholar
  58. Gonzalez-Gay, M.A., De Matias, J.M., Gonzalez-Juanatey, C., et al. (2006). Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 24:83–86.PubMedGoogle Scholar
  59. Goransson, O., McBride, A., Hawley, S.A., et al. (2007). Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282:32549–32560.PubMedCrossRefGoogle Scholar
  60. Guertin, D.A. and Sabatini, D.M. (2007). Defining the role of mTOR in cancer. Cancer Cell 12:9–22.PubMedCrossRefGoogle Scholar
  61. Guigas, B., Bertrand, L., Taleux, N., et al. (2006). 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation. Diabetes 55:865–874.PubMedCrossRefGoogle Scholar
  62. Gwinn, D.M., Shackelford, D.B., Egan, D.F., et al. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226.PubMedCrossRefGoogle Scholar
  63. Habets, D.D., Coumans, W.A., Voshol, P.J., et al. (2007). AMPK-mediated increase in myocardial long-chain fatty acid uptake critically depends on sarcolemmal CD36. Biochem. Biophys. Res. Commun. 355:204–210.PubMedCrossRefGoogle Scholar
  64. Hanahan, D. and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100:57–70.PubMedCrossRefGoogle Scholar
  65. Hardie, D.G. and Hawley, S.A. (2001). AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays 23:1112–1119.PubMedCrossRefGoogle Scholar
  66. Hawley, S.A., Davison, M., Woods, A., et al. (1996). Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271:27879–27887.PubMedCrossRefGoogle Scholar
  67. Hawley, S.A., Gadalla, A.E., Olsen, G.S., et al. (2002). The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51:2420–2425.PubMedCrossRefGoogle Scholar
  68. Hawley, S.A., Boudeau, J., Reid, J.L., et al. (2003). Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2:28.PubMedCrossRefGoogle Scholar
  69. Hawley, S.A., Pan, D.A., Mustard, K.J., et al. (2005). Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2:9–19.PubMedCrossRefGoogle Scholar
  70. Hemminki, A., Markie, D., Tomlinson, I., et al. (1998). A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187.PubMedCrossRefGoogle Scholar
  71. Holmes, B.F., Kurth-Kraczek, E.J., and Winder, W.W. (1999). Chronic activation of 5’-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J. Appl. Physiol. 87:1990–1995.PubMedGoogle Scholar
  72. Hong, Y.H., Varanasi, U.S., Yang, W. et al. (2003). AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem. 278:27495–27501.PubMedCrossRefGoogle Scholar
  73. Hudson, E.R., Pan, D.A., James, J., et al. (2003). A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13:861–866.PubMedCrossRefGoogle Scholar
  74. Hurley, R.L., Anderson, K.A., Franzone, J.M., et al. (2005). The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280:29060–29066.PubMedCrossRefGoogle Scholar
  75. Imamura, K., Ogura, T., Kishimoto, A., et al. (2001). Cell cycle regulation via p53 phosphorylation by a 5’-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem. Biophys. Res. Commun. 287:562–567.PubMedCrossRefGoogle Scholar
  76. Inoki, K., Li, Y., Zhu, T., et al. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol. 4:648–657.PubMedCrossRefGoogle Scholar
  77. Inoki, K., Zhu, T., and Guan, K.L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–590.PubMedCrossRefGoogle Scholar
  78. Iseli, T.J., Walter, M., van Denderen, B.J., et al. (2005). AMP-activated protein kinase beta subunit tethers alpha and gamma subunits via its C-terminal sequence (186-270). J. Biol. Chem. 280:13395–13400.PubMedCrossRefGoogle Scholar
  79. Iseli, T.J., Oakhill, J.S., Bailey, M.F., et al. (2008). AMP-activated protein kinase subunit interactions: beta1:gamma1 association requires beta1 Thr-263 and Tyr-267. J. Biol. Chem. 283:4799–4807.PubMedCrossRefGoogle Scholar
  80. Iverson, A.J., Bianchi, A., Nordlund, A.C., et al. (1990). Immunological analysis of acetyl-CoA carboxylase mass, tissue distribution and subunit composition. Biochem. J. 269:365–371.PubMedGoogle Scholar
  81. Jager, S., Handschin, C., St-Pierre, J., et al. (2007). AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc. Natl. Acad. Sci. USA 104:12017–12022.PubMedCrossRefGoogle Scholar
  82. Jin, X., Townley, R., Shapiro, L. (2007). Structural insight into AMPK regulation: ADP comes into play. Structure 15:1285–1295.PubMedCrossRefGoogle Scholar
  83. Johnson, L.N., Noble, M.E., Owen, D.J. (1996). Active and inactive protein kinases: structural basis for regulation. Cell 85:149–158.PubMedCrossRefGoogle Scholar
  84. Jones, R.G., Plas, D.R., Kubek, S., et al. (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18:283–293.PubMedCrossRefGoogle Scholar
  85. Jorgensen, S.B., Nielsen, J.N., Birk, J.B., et al. (2004a). The alpha2-5’AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading. Diabetes 53:3074–3081.PubMedCrossRefGoogle Scholar
  86. Jorgensen, S.B., Viollet, B., Andreelli, F., et al. (2004b). Knockout of the alpha2 but not alpha1 5’-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside but not contraction-induced glucose uptake in skeletal muscle. J. Biol. Chem. 279:1070–1079.PubMedCrossRefGoogle Scholar
  87. Jorgensen, S.B., Treebak, J.T., Viollet, B., et al. (2007). Role of AMPKalpha2 in basal, training-, and AICAR-induced GLUT4, hexokinase II, and mitochondrial protein expression in mouse muscle. Am. J. Physiol. Endocrinol. Metab. 292:E331–E339.PubMedCrossRefGoogle Scholar
  88. Kahn, B.B., Alquier, T., Carling, D. et al. (2005). AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1:15–25.PubMedCrossRefGoogle Scholar
  89. Kemp, B.E., Parker, M.W., Hu, S., et al. (1994). Substrate and pseudosubstrate interactions with protein kinases: determinants of specificity. Trends Biochem. Sci. 19:440–444.PubMedCrossRefGoogle Scholar
  90. Kim, M.S., Fielitz, J., McAnally, J., et al. (2008). Protein kinase D1 stimulates MEF2 activity in skeletal muscle and enhances muscle performance. Mol. Cell. Biol. 28:3600–3609.PubMedCrossRefGoogle Scholar
  91. Kloner, R.A. and Jennings, R.B. (2001). Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation 104:2981–2989.PubMedCrossRefGoogle Scholar
  92. Koay, A., Rimmer, K.A., Mertens, H.D., et al. (2007). Oligosaccharide recognition and binding to the carbohydrate binding module of AMP-activated protein kinase. FEBS Lett. 581:5055–5059.PubMedCrossRefGoogle Scholar
  93. Kola, B., Hubina, E., Tucci, S.A., et al. (2005). Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J. Biol. Chem. 280:25196–25201.PubMedCrossRefGoogle Scholar
  94. Kola, B., Boscaro, M., Rutter, G.A., et al. (2006). Expanding role of AMPK in endocrinology. Trends Endocrinol. Metab. 17:205–215.PubMedCrossRefGoogle Scholar
  95. Koo, S.H., Flechner, L., Qi, L., et al. (2005). The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437:1109–1111.PubMedCrossRefGoogle Scholar
  96. Kraegen, E.W. and Cooney, G.J. (2008). Free fatty acids and skeletal muscle insulin resistance. Curr. Opin. Lipidol. 19:235–241.PubMedCrossRefGoogle Scholar
  97. Kramer, H.F., Witczak, C.A., Fujii, N., et al. (2006). Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 55:2067–2076.PubMedCrossRefGoogle Scholar
  98. Kubota, N., Yano, W., Kubota, T., et al. (2007). Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6:55–68.PubMedCrossRefGoogle Scholar
  99. Leclerc, I., Kahn, A., and Doiron, B. (1998). The 5’-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex. FEBS Lett. 431:180–184.PubMedCrossRefGoogle Scholar
  100. Leclerc, I., Lenzner, C., Gourdon, L., et al. (2001). Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 50:1515–1521.PubMedCrossRefGoogle Scholar
  101. Lee, Y., Yu, X., Gonzales, F., et al. (2002). PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc. Natl. Acad. Sci. USA 99:11848–11853.PubMedCrossRefGoogle Scholar
  102. Lee, Y., Naseem, R.H., Park, B.H., et al. (2006a). Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem. Biophys. Res. Commun. 344:446–452.PubMedCrossRefGoogle Scholar
  103. Lee, Y.S., Kim, W.S., Kim, K.H., et al. (2006b). Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55:2256–2264.PubMedCrossRefGoogle Scholar
  104. Lee, J.H., Koh, H., Kim, M., et al. (2007). Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447:1017–1020.PubMedCrossRefGoogle Scholar
  105. Levine, A.J. (1997). p53, the cellular gatekeeper for growth and division. Cell 88:323–331.PubMedCrossRefGoogle Scholar
  106. Lizcano, J.M., Goransson, O., Toth, R., et al. (2004). LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 23:833–843.PubMedCrossRefGoogle Scholar
  107. Lochhead, P.A., Salt, I.P., Walker, K.S., et al. (2000). 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49:896–903.PubMedCrossRefGoogle Scholar
  108. Lopaschuk, G.D., Wambolt, R.B., and Barr, R.L. (1993). An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J. Pharmacol. Exp. Ther. 264:135–144.PubMedGoogle Scholar
  109. Luiken, J.J., Coort, S.L., Willems, J., et al. (2003). Contraction-induced fatty acid translocase/CD36 translocation in rat cardiac myocytes is mediated through AMP-activated protein kinase signaling. Diabetes 52:1627–1634.PubMedCrossRefGoogle Scholar
  110. Luptak, I., Shen, M., He, H., et al. (2007). Aberrant activation of AMP-activated protein kinase remodels metabolic network in favor of cardiac glycogen storage. J. Clin. Invest. 117:1432–1439.PubMedCrossRefGoogle Scholar
  111. Marsin, A.S., Bertrand, L., Rider, M.H., et al. (2000). Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 10:1247–1255.PubMedCrossRefGoogle Scholar
  112. Marsin, A.S., Bouzin, C., Bertrand, L. et al. (2002). The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J. Biol. Chem. 277:30778–30783.PubMedCrossRefGoogle Scholar
  113. Martin, S.G. and St Johnston, D. (2003). A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421:379–384.PubMedCrossRefGoogle Scholar
  114. Matthews, V.B. and Febbraio, M.A. (2008). CNTF: a target therapeutic for obesity-related metabolic disease? J. Mol. Med. 86:353–361.PubMedCrossRefGoogle Scholar
  115. McBride, A., Ghilagaber, S., Nikolaev, A., et al. (2009). The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9:23–34.PubMedCrossRefGoogle Scholar
  116. McGee, S.L. and Hargreaves, M. (2008). AMPK and transcriptional regulation. Front. Biosci. 13:3022–3033.PubMedCrossRefGoogle Scholar
  117. McTaggart, S.J. (2006). Isoprenylated proteins. Cell. Mol. Life Sci. 63:255–267.PubMedCrossRefGoogle Scholar
  118. Merrill, G.F., Kurth, E.J., Hardie, D.G., et al. (1997). AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol. 273:E1107–E1112.PubMedGoogle Scholar
  119. Minokoshi, Y., Kim, Y.B., Peroni, O.D., et al. (2002). Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415:339–343.PubMedCrossRefGoogle Scholar
  120. Minokoshi, Y., Alquier, T., Furukawa, N., et al. (2004). AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574.PubMedCrossRefGoogle Scholar
  121. Mitchelhill, K.I., Stapleton, D., Gao, G., et al. (1994). Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J. Biol. Chem. 269:2361–2364.PubMedGoogle Scholar
  122. Mitchelhill, K.I., Michell, B.J., House, C.M., et al. (1997). Posttranslational modifications of the 5’-AMP-activated protein kinase beta1 subunit. J. Biol. Chem. 272:24475–24479.PubMedCrossRefGoogle Scholar
  123. Momcilovic, M., Hong, S.P., Carlson, M. (2006). Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J. Biol. Chem. 281:25336–25343.PubMedCrossRefGoogle Scholar
  124. Mootha, V.K., Lindgren, C.M., Eriksson, K.F., et al. (2003). PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34:267–273.PubMedCrossRefGoogle Scholar
  125. Mu, J., Brozinick, J.T., Jr., Valladares, O., et al. (2001). A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell 7:1085–1094.PubMedCrossRefGoogle Scholar
  126. Muoio, D.M., Seefeld, K., Witters, L.A., et al. (1999). AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target. Biochem. J. 338:783–791.PubMedCrossRefGoogle Scholar
  127. Nilsson, E.C., Long, Y.C., Martinsson, S., et al. (2006). Opposite transcriptional regulation in skeletal muscle of AMP-activated protein kinase gamma3 R225Q transgenic versus knock-out mice. J. Biol. Chem. 281:7244–7252.PubMedCrossRefGoogle Scholar
  128. Ouchi, N., Kihara, S., Arita, Y., et al. (2001). Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103:1057–1063.PubMedCrossRefGoogle Scholar
  129. Owen, M.R., Doran, E., and Halestrap, A.P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348:607–614.PubMedCrossRefGoogle Scholar
  130. Pang, T., Xiong, B., Li, J.Y., et al. (2007). Conserved alpha-helix acts as autoinhibitory sequence in AMP-activated protein kinase alpha subunits. J. Biol. Chem. 282:495–506.PubMedCrossRefGoogle Scholar
  131. Parker, G.J., Koay, A., Gilbert-Wilson, R., et al. (2007). AMP-activated protein kinase does not associate with glycogen alpha-particles from rat liver. Biochem. Biophys. Res. Commun. 362:811–815.PubMedCrossRefGoogle Scholar
  132. Paterson, J., Kelsall, I.R., Cohen, P.T. (2008). Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: influence of the genetic background. J. Mol. Endocrinol. 40:47–59.PubMedCrossRefGoogle Scholar
  133. Polekhina, G., Gupta, A., Michell, B.J., et al. (2003). AMPK beta subunit targets metabolic stress sensing to glycogen. Curr. Biol. 13:867–871.PubMedCrossRefGoogle Scholar
  134. Polekhina, G., Gupta, A., van Denderen, B.J., et al. (2005). Structural basis for glycogen recognition by AMP-activated protein kinase. Structure 13:1453–1462.PubMedCrossRefGoogle Scholar
  135. Richards, A.A., Stephens, T., Charlton, H.K., et al. (2006). Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: evidence for regulation of multimerization by alterations in posttranslational modifications. Mol. Endocrinol. 20:1673–1687.PubMedCrossRefGoogle Scholar
  136. Rockl, K.S., Hirshman, M.F., Brandauer, J., Fujii, N., Witters, L.A., and Goodyear, L.J. (2007). Skeletal muscle adaptation to exercise training: AMP-activated protein kinase mediates muscle fiber type shift. Diabetes 56:2062–2069.PubMedCrossRefGoogle Scholar
  137. Ryder, J.W., Bassel-Duby, R., Olson, E.N., et al. (2003). Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways. J. Biol. Chem. 278:44298–44304.PubMedCrossRefGoogle Scholar
  138. Saghizadeh, M., Ong, J.M., Garvey, W.T., et al. (1996). The expression of TNF alpha by human muscle. Relationship to insulin resistance. J. Clin. Invest. 97:1111–1116.PubMedCrossRefGoogle Scholar
  139. Sakamoto, K. and Holman, G.D. (2008). Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. Am. J. Physiol. Endocrinol. Metab. 295:E29–E37.PubMedCrossRefGoogle Scholar
  140. Sanders, M.J., Ali, Z.S., Hegarty, B.D., et al. (2007a). Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem. 282:32539–32548.PubMedCrossRefGoogle Scholar
  141. Sanders, M.J., Grondin, P.O., Hegarty, B.D., et al. (2007b). Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403:139–148.PubMedCrossRefGoogle Scholar
  142. Sapkota, G.P., Kieloch, A., Lizcano, J.M., et al. (2001). Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell growth. J. Biol. Chem. 276:19469–19482.PubMedCrossRefGoogle Scholar
  143. Scheidereit, C. (2006). IkappaB kinase complexes: gateways to NF-kappaB activation and transcription. Oncogene 25:6685–6705.PubMedCrossRefGoogle Scholar
  144. Schmelzle, T. and Hall, M.N. (2000). TOR, a central controller of cell growth. Cell 103:253–262.PubMedCrossRefGoogle Scholar
  145. Scott, J.W., Norman, D.G., Hawley, S.A., et al. (2002). Protein kinase substrate recognition studied using the recombinant catalytic domain of AMP-activated protein kinase and a model substrate. J. Mol. Biol. 317:309–323.PubMedCrossRefGoogle Scholar
  146. Scott, J.W., Hawley, S.A., Green, K.A., et al. (2004). CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J. Clin. Invest. 113:274–284.PubMedGoogle Scholar
  147. Scott, J.W., Ross, F.A., Liu, J.K. et al. (2007). Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit. EMBO J. 26:806–815.PubMedCrossRefGoogle Scholar
  148. Scott, J.W., van Denderen, B.J., Jorgensen, S.B., et al. (2008). Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. Chem. Biol. 15:1220–1230.PubMedCrossRefGoogle Scholar
  149. Scott, J.W., Oakhill, J.S., and van Denderen, B.J. (2009). AMPK/SNF1 structure: a menage a trois of energy-sensing. Front. Biosci. 14:596–610.PubMedCrossRefGoogle Scholar
  150. Shaw, R.J., Lamia, K.A., Vasquez, D., et al. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646.PubMedCrossRefGoogle Scholar
  151. Stahmann, N., Woods, A., Carling, D. et al. (2006). Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase beta. Mol. Cell Biol. 26:5933–5945.PubMedCrossRefGoogle Scholar
  152. Steinberg, G.R., Rush, J.W., and Dyck, D.J. (2003). AMPK expression and phosphorylation are increased in rodent muscle after chronic leptin treatment. Am. J. Physiol. Endocrinol. Metab. 284:E648–E654.PubMedGoogle Scholar
  153. Steinberg, G.R., Michell, B.J., van Denderen, B.J., et al. (2006). Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab. 4:465–474.PubMedCrossRefGoogle Scholar
  154. Steinberg, G.R., Watt, M.J., and Febbraio, M.A. (2009). Cytokine regulation of AMPK signalling. Front. Biosci. 14:1902–1916.PubMedCrossRefGoogle Scholar
  155. Suter, M., Riek, U., Tuerk, R., et al. (2006). Dissecting the role of 5’-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281:32207–32216.PubMedCrossRefGoogle Scholar
  156. Suzuki, A., Kusakai, G., Shimojo, Y., et al. (2005). Involvement of transforming growth factor-beta 1 signaling in hypoxia-induced tolerance to glucose starvation. J. Biol. Chem. 280:31557–31563.PubMedCrossRefGoogle Scholar
  157. Tamas, P., Hawley, S.A., Clarke, R.G., et al. (2006). Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203:1665–1670.PubMedCrossRefGoogle Scholar
  158. Tan, M.J., Ye, J.M., Turner, N., et al. (2008). Antidiabetic activities of triterpenoids isolated from bitter melon associated with activation of the AMPK pathway. Chem. Biol. 15:263–273.PubMedCrossRefGoogle Scholar
  159. Thomson, D.M., Porter, B.B., Tall, J.H., et al. (2007). Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice. Am. J. Physiol. Endocrinol. Metab. 292:E196–E202.PubMedCrossRefGoogle Scholar
  160. Tokumitsu, H., Iwabu, M., Ishikawa, Y., et al. (2001). Differential regulatory mechanism of Ca2+/calmodulin-dependent protein kinase kinase isoforms. Biochemistry 40:13925–13932.PubMedCrossRefGoogle Scholar
  161. Tomas, E., Tsao, T.S., Saha, A.K., et al. (2002). Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc. Natl. Acad. Sci. USA 99:16309–16313.PubMedCrossRefGoogle Scholar
  162. Treebak, J.T., Glund, S., Deshmukh, A., et al. (2006). AMPK-mediated AS160 phosphorylation in skeletal muscle is dependent on AMPK catalytic and regulatory subunits. Diabetes 55:2051–2058.PubMedCrossRefGoogle Scholar
  163. Turner, N., Li, J.Y., Gosby, A., et al. (2008). Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 57:1414–1418.PubMedCrossRefGoogle Scholar
  164. van Slegtenhorst, M., Nellist, M., Nagelkerken, B., et al. (1998). Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7:1053–1057.PubMedCrossRefGoogle Scholar
  165. Vincent, M.F., Marangos, P.J., Gruber, H.E., et al. (1991). Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40:1259–1266.PubMedCrossRefGoogle Scholar
  166. Viollet, B., Andreelli, F., Jorgensen, S.B., et al. (2003). The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111:91–98.PubMedGoogle Scholar
  167. Virbasius, J.V. and Scarpulla, R.C. (1994). Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl. Acad. Sci. USA 91:1309–1313.PubMedCrossRefGoogle Scholar
  168. Wang, M.Y., Orci, L., Ravazzola, M., et al. (2005). Fat storage in adipocytes requires inactivation of leptin’s paracrine activity: implications for treatment of human obesity. Proc. Natl. Acad. Sci. USA 102:18011–18016.PubMedCrossRefGoogle Scholar
  169. Wang, C., Mao, X., Wang, L., et al. (2007). Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J. Biol. Chem. 282:7991–7996.PubMedCrossRefGoogle Scholar
  170. Warburg, O. (1956). On the origin of cancer cells. Science 123:309–314.PubMedCrossRefGoogle Scholar
  171. Warden, S.M., Richardson, C., O’Donnell, J. Jr., et al. (2001). Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem J. 354:275–283.PubMedCrossRefGoogle Scholar
  172. Watt, M.J., Dzamko, N., Thomas, W.G., et al. (2006). CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat. Med. 12:541–548.PubMedCrossRefGoogle Scholar
  173. Williams, T. and Brenman, J.E. (2008). LKB1 and AMPK in cell polarity and division. Trends Cell Biol. 18:193–198.PubMedCrossRefGoogle Scholar
  174. Winder, W.W., Holmes, B.F., Rubink, D.S., et al. (2000). Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88:2219–2226.PubMedGoogle Scholar
  175. Wisneski, J.A., Gertz, E.W., Neese, R.A., et al. (1987). Myocardial metabolism of free fatty acids. Studies with 14C-labeled substrates in humans. J. Clin. Invest. 79:359–366.PubMedCrossRefGoogle Scholar
  176. Wojtaszewski, J.F., Nielsen, P., Hansen, B.F., et al. (2000). Isoform-specific and exercise intensity-dependent activation of 5’-AMP-activated protein kinase in human skeletal muscle. J. Physiol. 528:221–226.PubMedCrossRefGoogle Scholar
  177. Wojtaszewski, J.F., Mourtzakis, M., Hillig, T., et al. (2002). Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise. Biochem. Biophys. Res. Commun. 298:309–316.PubMedCrossRefGoogle Scholar
  178. Woods, A., Munday, M.R., Scott, J., et al. (1994). Yeast SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates acetyl-CoA carboxylase in vivo. J. Biol. Chem. 269:19509–19515.PubMedGoogle Scholar
  179. Woods, A., Azzout-Marniche, D., Foretz, M., et al. (2000). Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol. Cell. Biol. 20:6704–6711.PubMedCrossRefGoogle Scholar
  180. Woods, A., Dickerson, K., Heath, R., et al. (2005). Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2:21–33.PubMedCrossRefGoogle Scholar
  181. Wu, X., Motoshima, H., Mahadev, K., et al. (2003). Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes 52:1355–1363.PubMedCrossRefGoogle Scholar
  182. Wullschleger, S., Loewith, R., and Hall, M.N. (2006). TOR signaling in growth and metabolism. Cell, 124:471–484.PubMedCrossRefGoogle Scholar
  183. Xiao, B., Heath, R., Saiu, P., et al. (2007). Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449:496–500.PubMedCrossRefGoogle Scholar
  184. Xu, K.Y., Zweier, J.L., and Becker, L.C. (1995). Functional coupling between glycolysis and sarcoplasmic reticulum Ca2+ transport. Circ. Res. 77:88–97.PubMedCrossRefGoogle Scholar
  185. Yamauchi, T., Kamon, J., Minokoshi, Y., et al. (2002). Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8:1288–1295.PubMedCrossRefGoogle Scholar
  186. Yamauchi, T., Nio, Y., Maki, T., et al. (2007). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13:332–339.PubMedCrossRefGoogle Scholar
  187. Young, M.E., Radda, G.K., and Leighton, B. (1996). Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR- an activator of AMP-activated protein kinase. FEBS Lett. 382:43–47.PubMedCrossRefGoogle Scholar
  188. Zakikhani, M., Dowling, R., Fantus, I.G., et al. (2006). Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66:10269–10273.PubMedCrossRefGoogle Scholar
  189. Zhou, G., Myers, R., Li, Y., et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108:1167–1174.PubMedGoogle Scholar
  190. Zhou, G., Sebhat, I.K., and Zhang, B.B. (2009). AMPK activators. Potential therapeutics for metabolic and other diseases. Acta Physiol. (Oxf) 196:175–190.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.St Vincent’s Institute and Department of MedicineUniversity of MelbourneFitzroyAustralia

Personalised recommendations