Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer

Biochimica et Biophysica Acta - Proteins and Proteomics

Volumn 1804, Issue 3, 2010, Pages 581-591

  Fogarty, S ^a   Hardie, D G ^a  

^a UNIVERSITY OF DUNDEE   (United Kingdom)

Author keywords

Activator; AMPK; Cancer; Diabetes; Metabolic Syndrome; Obesity

Indexed keywords

5 AMINO 4 IMIDAZOLECARBOXAMIDE RIBOSIDE; 6,7 DIHYDRO 4 HYDROXY 3 (2' HYDROXY 1,1' BIPHENYL 4 YL) 6 OXOTHIENO[2,3 B]PYRIDINE 5 CARBONITRILE; ADENOSINE PHOSPHATE; ADENOSINE TRIPHOSPHATE; ADENYLATE KINASE; ADIPOCYTOKINE; ADIPONECTIN; BERBERINE; CURCUMIN; ENZYME ACTIVATOR; FATTY ACID; GALEGINE; GINSENOSIDE; GLUCOSE; GLUCOSE TRANSPORTER 1; GLUCOSE TRANSPORTER 4; INSULIN; ISOGINKGETIN; METFORMIN; OCTAMER TRANSCRIPTION FACTOR 1; PHENFORMIN; PIOGLITAZONE; PLANT MEDICINAL PRODUCT; PT 1; QUERCETIN; RESVERATROL; ROSIGLITAZONE; TRIACYLGLYCEROL; TRITERPENOID; TROGLITAZONE; UNCLASSIFIED DRUG;

ABDOMINAL FAT; ADIPOCYTE; ADIPOSE TISSUE; AGING; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER INHIBITION; CANCER PREVENTION; CANCER SUSCEPTIBILITY; CELL ENERGY; CELL GROWTH; CELL PROLIFERATION; DIET RESTRICTION; DRUG BLOOD LEVEL; DRUG MECHANISM; DRUG UPTAKE; ENERGY CONSUMPTION; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME REGULATION; ENZYME STRUCTURE; FATTY ACID BLOOD LEVEL; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FOOD INTAKE; GENETIC VARIABILITY; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; GLUCOSE TRANSPORT; HUMAN; HYPOGLYCEMIA; INSULIN BLOOD LEVEL; INSULIN SENSITIVITY; LACTIC ACIDOSIS; LIPID METABOLISM; LIVER; LYMPHOMA; METABOLIC DISORDER; METABOLIC STRESS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOGENESIS; PRIORITY JOURNAL; PROSTATE CANCER; REVIEW; SKELETAL MUSCLE; SURVIVAL; TRIACYLGLYCEROL BLOOD LEVEL; WEIGHT REDUCTION;

ADENOSINE TRIPHOSPHATE; AMP-ACTIVATED PROTEIN KINASES; ANIMALS; CELL PROLIFERATION; DRUG DELIVERY SYSTEMS; DRUG DESIGN; ENERGY METABOLISM; ENZYME ACTIVATORS; FATTY ACIDS; GLUCONEOGENESIS; HUMANS; METABOLIC DISEASES; NEOPLASMS;

EID: 75349099919     PISSN: 15709639     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bbapap.2009.09.012     Document Type: Review

References (163)

1. Eckel R.H., Grundy S.M., and Zimmet P.Z. The metabolic syndrome. Lancet 365 (2005) 1415-1428
2. Dossus L., and Kaaks R. Nutrition, metabolic factors and cancer risk. Best Pract. Res. Clin. Endocrinol. Metab. 22 (2008) 551-571
3. Miranda-Saavedra D., Stark M.J., Packer J.C., Vivares C.P., Doerig C., and Barton G.J. The complement of protein kinases of the microsporidium Encephalitozoon cuniculi in relation to those of Saccharomyces cerevisiae and Schizosaccharomyces pombe. BMC Genomics 8 (2007) 309
4. Hardie D.G., Carling D., and Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell?. Ann. Rev. Biochem. 67 (1998) 821-855
5. Thelander M., Olsson T., and Ronne H. Snf1-related protein kinase 1 is needed for growth in a normal day-night light cycle. EMBO J. 23 (2004) 1900-1910
6. Apfeld J., O'Connor G., McDonagh T., Distefano P.S., and Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18 (2004) 3004-3009
7. Hardie D.G. AMP-activated protein kinase as a drug target. Annu. Rev. Pharmacol. Toxicol. 47 (2007) 185-210
8. Hardie D.G. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev., Mol. Cell Biol. 8 (2007) 774-785
9. Hardie D.G. Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582 (2008) 81-89
10. Dzamko N.L., and Steinberg G.R. AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol. (Oxf) 196 (2009) 115-127
11. Wang W., and Guan K.L. AMP-activated protein kinase and cancer. Acta Physiol. (Oxf) 196 (2009) 55-63
12. Hawley S.A., Davison M., Woods A., Davies S.P., Beri R.K., Carling D., and Hardie D.G. Characterization of the AMP-activated protein kinase kinase from rat liver, and identification of threonine-172 as the major site at which it phosphorylates and activates AMP-activated protein kinase. J. Biol. Chem. 271 (1996) 27879-27887
13. Stein S.C., Woods A., Jones N.A., Davison M.D., and Carling D. The regulation of AMP-activated protein kinase by phosphorylation. Biochem. J. 345 (2000) 437-443
14. Suter M., Riek U., Tuerk R., Schlattner U., Wallimann T., and Neumann D. Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281 (2006) 32207-32216
15. Crute B.E., Seefeld K., Gamble J., Kemp B.E., and Witters L.A. Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase. J. Biol. Chem. 273 (1998) 35347-35354
16. Pang T., Xiong B., Li J.Y., Qiu B.Y., Jin G.Z., Shen J.K., and Li J. Conserved alpha-helix acts as autoinhibitory sequence in AMP-activated protein kinase alpha subunits. J. Biol. Chem. 282 (2007) 495-506
17. Goransson O., McBride A., Hawley S.A., Ross F.A., Shpiro N., Foretz M., Viollet B., Hardie D.G., and Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282 (2007) 32549-32560
18. Chen L., Jiao Z.H., Zheng L.S., Zhang Y.Y., Xie S.T., Wang Z.X., and Wu J.W. Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature (2009)
19. Hudson E.R., Pan D.A., James J., Lucocq J.M., Hawley S.A., Green K.A., Baba O., Terashima T., and Hardie D.G. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13 (2003) 861-866
20. Polekhina G., Gupta A., Michell B.J., van Denderen B., Murthy S., Feil S.C., Jennings I.G., Campbell D.J., Witters L.A., Parker M.W., Kemp B.E., and Stapleton D. AMPK Δ-subunit targets metabolic stress-sensing to glycogen. Curr. Biol. 13 (2003) 867-871
21. McBride A., Ghilagaber S., Nikolaev A., and Hardie D.G. The glycogen-binding domain on AMP-activated protein kinase is a regulatory domain that allows the kinase to act as a sensor of glycogen structure. Cell Metab. 9 (2009) 23-34
22. Mitchelhill K.I., Michell B.J., House C.M., Stapleton D., Dyck J., Gamble J., Ullrich C., Witters L.A., and Kemp B.E. Posttranslational modifications of the 5′-AMP-activated protein kinase beta1 subunit. J. Biol. Chem. 272 (1997) 24475-24479
23. Sanders M.J., Ali Z.S., Hegarty B.D., Heath R., Snowden M.A., and Carling D. 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 (2007) 32539-32548
24. Scott J.W., Hawley S.A., Green K.A., Anis M., Stewart G., Scullion G.A., Norman D.G., and Hardie D.G. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J. Clin. Invest. 113 (2004) 274-284
25. Xiao B., Heath R., Saiu P., Leiper F.C., Leone P., Jing C., Walker P.A., Haire L., Eccleston J.F., Davis C.T., Martin S.R., Carling D., and Gamblin S.J. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449 (2007) 496-500
26. Corton J.M., Gillespie J.G., Hawley S.A., and Hardie D.G. 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells?. Eur. J. Biochem. 229 (1995) 558-565
27. Sanders M.J., Grondin P.O., Hegarty B.D., Snowden M.A., and Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403 (2007) 139-148
28. C. FEBS Lett. 377 (1995) 421-425
29. Shaw R.J., Kosmatka M., Bardeesy N., Hurley R.L., Witters L.A., DePinho R.A., and Cantley L.C. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 3329-3335
30. Hawley S.A., Boudeau J., Reid J.L., Mustard K.J., Udd L., Makela T.P., Alessi D.R., and Hardie D.G. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2 (2003) 28
31. Woods A., Johnstone S.R., Dickerson K., Leiper F.C., Fryer L.G., Neumann D., Schlattner U., Wallimann T., Carlson M., and Carling D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13 (2003) 2004-2008
32. Hawley S.A., Pan D.A., Mustard K.J., Ross L., Bain J., Edelman A.M., Frenguelli B.G., and Hardie D.G. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2 (2005) 9-19
33. Woods A., Dickerson K., Heath R., Hong S.P., Momcilovic M., Johnstone S.R., Carlson M., and Carling D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2 (2005) 21-33
34. 2+/calmoldulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280 (2005) 29060-29066
35. Alessi D.R., Sakamoto K., and Bayascas J.R. Lkb1-dependent signaling pathways. Annu. Rev. Biochem. 75 (2006) 137-163
36. Momcilovic M., Hong S.P., and Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J. Biol. Chem. 281 (2006) 25336-25343
37. Herrero-Martin G., Hoyer-Hansen M., Garcia-Garcia C., Fumarola C., Farkas T., Lopez-Rivas A., and Jaattela M. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28 (2009) 677-685
38. Merrill G.M., Kurth E., Hardie D.G., and Winder W.W. AICAR decreases malonyl-CoA and increases fatty acid oxidation in skeletal muscle of the rat. Am. J. Physiol. 273 (1997) E1107-E1112
39. Kurth-Kraczek E.J., Hirshman M.F., Goodyear L.J., and Winder W.W. 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48 (1999) 1667-1671
40. Treebak J.T., Glund S., Deshmukh A., Klein D.K., Long Y.C., Jensen T.E., Jorgensen S.B., Viollet B., Andersson L., Neumann D., Wallimann T., Richter E.A., Chibalin A.V., Zierath J.R., and Wojtaszewski J.F. AMPK-mediated AS160 phosphorylation in skeletal muscle Is dependent on AMPK catalytic and regulatory subunits. Diabetes 55 (2006) 2051-2058
41. Kramer H.F., Witczak C.A., Fujii N., Jessen N., Taylor E.B., Arnolds D.E., Sakamoto K., Hirshman M.F., and Goodyear L.J. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 55 (2006) 2067-2076
42. Chavez J.A., Roach W.G., Keller S.R., Lane W.S., and Lienhard G.E. 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 (2008) 9187-9195
43. Taylor E.B., An D., Kramer H.F., Yu H., Fujii N.L., Roeckl K.S., Bowles N., Hirshman M.F., Xie J., Feener E.P., and Goodyear L.J. Discovery of TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling nexus in mouse skeletal muscle. J. Biol. Chem. 283 (2008) 9787-9796
44. Chen S., Murphy J., Toth R., Campbell D.G., Morrice N.A., and Mackintosh C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem. J. 409 (2008) 449-459
45. Barnes K., Ingram J.C., Porras O.H., Barros L.F., Hudson E.R., Fryer L.G., Foufelle F., Carling D., Hardie D.G., and Baldwin S.A. Activation of GLUT1 by metabolic and osmotic stress: potential involvement of AMP-activated protein kinase (AMPK). J. Cell. Sci. 115 (2002) 2433-2442
46. Zheng D., MacLean P.S., Pohnert S.C., Knight J.B., Olson A.L., Winder W.W., and Dohm G.L. Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J. Appl. Physiol. 91 (2001) 1073-1083
47. Jager S., Handschin C., St-Pierre J., and Spiegelman B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1{alpha}. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 12017-12022
48. Holmes B.F., Sparling D.P., Olson A.L., Winder W.W., and Dohm G.L. Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase. Am. J. Physiol. Endocrinol. Metab. 289 (2005) E1071-1076
49. McGee S.L. Exercise and MEF2-HDAC interactions. Appl. Physiol. Nutr. Metab. 32 (2007) 852-856
50. Narkar V.A., Downes M., Yu R.T., Embler E., Wang Y.X., Banayo E., Mihaylova M.M., Nelson M.C., Zou Y., Juguilon H., Kang H., Shaw R.J., and Evans R.M. AMPK and PPARdelta agonists are exercise mimetics. Cell (2008)
51. Mu J., Brozinick J.T., Valladares O., Bucan M., and Birnbaum M.J. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell 7 (2001) 1085-1094
52. Sakamoto K., McCarthy A., Smith D., Green K.A., Hardie D.G., Ashworth A., and Alessi D.R. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 24 (2005) 1810-1820
53. Jorgensen S.B., Viollet B., Andreelli F., Frosig C., Birk J.B., Schjerling P., Vaulont S., Richter E.A., and Wojtaszewski J.F. 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 (2004) 1070-1079
54. Winder W.W., Holmes B.F., Rubink D.S., Jensen E.B., Chen M., and Holloszy J.O. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J. Appl. Physiol. 88 (2000) 2219-2226
55. Lowell B.B., and Shulman G.I. Mitochondrial dysfunction and type 2 diabetes. Science 307 (2005) 384-387
56. Lochhead P.A., Salt I.P., Walker K.S., Hardie D.G., and Sutherland C. 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 (2000) 896-903
57. Yamauchi T., Kamon J., Minokoshi Y., Ito Y., Waki H., Uchida S., Yamashita S., Noda M., Kita S., Ueki K., Eto K., Akanuma Y., Froguel P., Foufelle F., Ferre P., Carling D., Kimura S., Nagai R., Kahn B.B., and Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 6 (2002) 1288-1295
58. Cool B., Zinker B., Chiou W., Kifle L., Cao N., Perham M., Dickinson R., Adler A., Gagne G., Iyengar R., Zhao G., Marsh K., Kym P., Jung P., Camp H.S., and Frevert E. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 3 (2006) 403-416
59. Mayr B.M., Canettieri G., and Montminy M.R. Distinct effects of cAMP and mitogenic signals on CREB-binding protein recruitment impart specificity to target gene activation via CREB. Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 10936-10941
60. Nakae J., Cao Y., Oki M., Orba Y., Sawa H., Kiyonari H., Iskandar K., Suga K., Lombes M., and Hayashi Y. Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure. Diabetes 57 (2008) 563-576
61. Hirota K., Sakamaki J., Ishida J., Shimamoto Y., Nishihara S., Kodama N., Ohta K., Yamamoto M., Tanimoto K., and Fukamizu A. A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding. J. Biol. Chem. 283 (2008) 32432-32441
62. Koo S.H., Flechner L., Qi L., Zhang X., Screaton R.A., Jeffries S., Hedrick S., Xu W., Boussouar F., Brindle P., Takemori H., and Montminy M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437 (2005) 1109-1114
63. He L., Sabet A., Djedjos S., Miller R., Sun X., Hussain M.A., Radovick S., and Wondisford F.E. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137 (2009) 635-646
64. Leclerc I., Lenzner C., Gourdon L., Vaulont S., Kahn A., and Viollet B. Hepatocyte nuclear factor-4α involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 50 (2001) 1515-1521
65. Barthel A., Schmoll D., Kruger K.D., Roth R.A., and Joost H.G. Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. Endocrinology 143 (2002) 3183-3186
66. Kim Y.D., Park K.G., Lee Y.S., Park Y.Y., Kim D.K., Nedumaran B., Jang W.G., Cho W.J., Ha J., Lee I.K., Lee C.H., and Choi H.S. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 57 (2008) 306-314
67. Zhou G., Myers R., Li Y., Chen Y., Shen X., Fenyk-Melody J., Wu M., Ventre J., Doebber T., Fujii N., Musi N., Hirshman M.F., Goodyear L.J., and Moller D.E. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108 (2001) 1167-1174
68. Foretz M., Ancellin N., Andreelli F., Saintillan Y., Grondin P., Kahn A., Thorens B., Vaulont S., and Viollet B. Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. Diabetes 54 (2005) 1331-1339
69. Kawaguchi T., Osatomi K., Yamashita H., Kabashima T., and Uyeda K. Mechanism for fatty acid "sparing" effect on glucose-induced transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. J. Biol. Chem. 277 (2002) 3829-3835
70. Daval M., Diot-Dupuy F., Bazin R., Hainault I., Viollet B., Vaulont S., Hajduch E., Ferre P., and Foufelle F. Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J. Biol. Chem. 280 (2005) 25250-25257
71. Winder W.W., and Hardie D.G. The AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. 277 (1999) E1-E10
72. Fryer L.G., Parbu-Patel A., and Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct pathways. J. Biol. Chem. 277 (2002) 25226-25232
73. Hawley S.A., Gadalla A.E., Olsen G.S., and Hardie D.G. The anti-diabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51 (2002) 2420-2425
74. Shaw R.J., Lamia K.A., Vasquez D., Koo S.H., Bardeesy N., Depinho R.A., Montminy M., and Cantley L.C. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310 (2005) 1642-1646
75. Sullivan J.E., Brocklehurst K.J., Marley A.E., Carey F., Carling D., and Beri R.K. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 353 (1994) 33-36
76. Gadalla A.E., Pearson T., Currie A.J., Dale N., Hawley S.A., Randall A.D., Hardie D.G., and Frenguelli B.G. Distinct mechanisms underlie the activation of rat brain AMP-activated protein kinase and the inhibition of excitatory synaptic transmission by AICA riboside (Acadesine) in area CA1 of rat hippocampus. J. Neurochem. 88 (2004) 1272-1282
77. Song X.M., Fiedler M., Galuska D., Ryder J.W., Fernström M., Chibalin A.V., Wallberg-Henriksson H., and Zierath J.R. 5-Aminoimidazole-4-caboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45 (2002) 56-65
78. Bergeron R., Previs S.F., Cline G.W., Perret P., Russell 3rd R.R., Young L.H., and Shulman G.I. 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 (2001) 1076-1082
79. Buhl E.S., Jessen N., Schmitz O., Pedersen S.B., Pedersen O., Holman G.D., and Lund S. Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes 50 (2001) 12-17
80. Iglesias M.A., Ye J.M., Frangioudakis G., Saha A.K., Tomas E., Ruderman N.B., Cooney G.J., and Kraegen E.W. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51 (2002) 2886-2894
81. Vincent M.F., Marangos P.J., Gruber H.E., and Van den Berghe G. Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40 (1991) 1259-1266
82. Longnus S.L., Wambolt R.B., Parsons H.L., Brownsey R.W., and Allard M.F. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am. J. Physiol. 284 (2003) R936-R944
83. Witters L.A. The blooming of the French lilac. J. Clin. Invest. 108 (2001) 1105-1107
84. Hundal R.S., Krssak M., Dufour S., Laurent D., Lebon V., Chandramouli V., Inzucchi S.E., Schumann W.C., Petersen K.F., Landau B.R., and Shulman G.I. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 49 (2000) 2063-2069
85. Owen M.R., Doran E., and Halestrap A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348 (2000) 607-614
86. El-Mir M.Y., Nogueira V., Fontaine E., Averet N., Rigoulet M., and Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275 (2000) 223-228
87. Wang D.S., Jonker J.W., Kato Y., Kusuhara H., Schinkel A.H., and Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302 (2002) 510-515
88. Shu Y., Sheardown S.A., Brown C., Owen R.P., Zhang S., Castro R.A., Ianculescu A.G., Yue L., Lo J.C., Burchard E.G., Brett C.M., and Giacomini K.M. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J. Clin. Invest. 117 (2007) 1422-1431
89. Mooney M.H., Fogarty S., Stevenson C., Gallagher A.M., Palit P., Hawley S.A., Hardie D.G., Coxon G.D., Waigh R.D., Tate R.J., Harvey A.L., and Furman B.L. Mechanisms underlying the metabolic actions of galegine that contribute to weight loss in mice. Br. J. Pharmacol. 153 (2008) 1669-1677
90. Lebrasseur N.K., Kelly M., Tsao T.S., Farmer S.R., Saha A.K., Ruderman N.B., and Tomas E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am. J. Physiol. Endocrinol. Metab. 291 (2006) E175-E181
91. Brunmair B., Staniek K., Gras F., Scharf N., Althaym A., Clara R., Roden M., Gnaiger E., Nohl H., Waldhausl W., and Furnsinn C. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions?. Diabetes 53 (2004) 1052-1059
92. Lehmann J.M., Moore L.B., Smith-Oliver T.A., Wilkison W.O., Willson T.M., and Kliewer S.A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270 (1995) 12953-12956
93. Maeda N., Takahashi M., Funahashi T., Kihara S., Nishizawa H., Kishida K., Nagaretani H., Matsuda M., Komuro R., Ouchi N., Kuriyama H., Hotta K., Nakamura T., Shimomura I., and Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50 (2001) 2094-2099
94. Kubota N., Terauchi Y., Kubota T., Kumagai H., Itoh S., Satoh H., Yano W., Ogata H., Tokuyama K., Takamoto I., Mineyama T., Ishikawa M., Moroi M., Sugi K., Yamauchi T., Ueki K., Tobe K., Noda T., Nagai R., and Kadowaki T. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J. Biol. Chem. 281 (2006) 8748-8755
95. Kim S.H., Shin E.J., Kim E.D., Bayaraa T., Frost S.C., and Hyun C.K. Berberine activates GLUT1-mediated glucose uptake in 3T3-L1 adipocytes. Biol. Pharm. Bull. 30 (2007) 2120-2125
96. Lee Y.S., Kim W.S., Kim K.H., Yoon M.J., Cho H.J., Shen Y., Ye J.M., Lee C.H., Oh W.K., Kim C.T., Hohnen-Behrens C., Gosby A., Kraegen E.W., James D.E., and Kim J.B. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55 (2006) 2256-2264
97. Yin J., Gao Z., Liu D., Liu Z., and Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am. J. Physiol. Endocrinol. Metab. (2007)
98. Turner N., Li J.Y., Gosby A., To S.W., Cheng Z., Miyoshi H., Taketo M.M., Cooney G.J., Kraegen E.W., James D.E., Hu L.H., Li J., and Ye J.M. 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 (2008) 1414-1418
99. Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G., Zipkin R.E., Chung P., Kisielewski A., Zhang L.L., Scherer B., and Sinclair D.A. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425 (2003) 191-196
100. Baur J.A., Pearson K.J., Price N.L., Jamieson H.A., Lerin C., Kalra A., Prabhu V.V., Allard J.S., Lopez-Lluch G., Lewis K., Pistell P.J., Poosala S., Becker K.G., Boss O., Gwinn D., Wang M., Ramaswamy S., Fishbein K.W., Spencer R.G., Lakatta E.G., Le Couteur D., Shaw R.J., Navas P., Puigserver P., Ingram D.K., de Cabo R., and Sinclair D.A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444 (2006) 337-342
101. Lagouge M., Argmann C., Gerhart-Hines Z., Meziane H., Lerin C., Daussin F., Messadeq N., Milne J., Lambert P., Elliott P., Geny B., Laakso M., Puigserver P., and Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127 (2006) 1109-1122
102. Dasgupta B., and Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 7217-7222
103. Park C.E., Kim M.J., Lee J.H., Min B.I., Bae H., Choe W., Kim S.S., and Ha J. Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp. Mol. Med. 39 (2007) 222-229
104. Fulco M., and Sartorelli V. Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7 (2008) 3669-3679
105. Canto C., Gerhart-Hines Z., Feige J.N., Lagouge M., Noriega L., Milne J.C., Elliott P.J., Puigserver P., and Auwerx J. AMPK regulates energy expenditure by modulating NAD(+) metabolism and SIRT1 activity. Nature 458 (2009) 1056-1060
106. Hou X., Xu S., Maitland-Toolan K.A., Sato K., Jiang B., Ido Y., Lan F., Walsh K., Wierzbicki M., Verbeuren T.J., Cohen R.A., and Zang M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J. Biol. Chem. 283 (2008) 20015-20026
107. Lan F., Cacicedo J.M., Ruderman N., and Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J. Biol. Chem. 283 (2008) 27628-27635
108. Feige J.N., Lagouge M., Canto C., Strehle A., Houten S.M., Milne J.C., Lambert P.D., Mataki C., Elliott P.J., and Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab. 8 (2008) 347-358
109. Suchankova G., Nelson L.E., Gerhart-Hines Z., Kelly M., Gauthier M.S., Saha A.K., Ido Y., Puigserver P., and Ruderman N.B. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem. Biophys. Res. Commun. 378 (2009) 836-841
110. Ahn J., Lee H., Kim S., Park J., and Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem. Biophys. Res. Commun. 373 (2008) 545-549
111. Fujiwara H., Hosokawa M., Zhou X., Fujimoto S., Fukuda K., Toyoda K., Nishi Y., Fujita Y., Yamada K., Yamada Y., Seino Y., and Inagaki N. Curcumin inhibits glucose production in isolated mice hepatocytes. Diabetes Res. Clin. Pract. 80 (2008) 185-191
112. Liu G., Grifman M., Macdonald J., Moller P., Wong-Staal F., and Li Q.X. Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase. J. Endocrinol. 194 (2007) 569-578
113. Hwang J.T., Lee M.S., Kim H.J., Sung M.J., Kim H.Y., Kim M.S., and Kwon D.Y. Antiobesity effect of ginsenoside Rg3 involves the AMPK and PPAR-gamma signal pathways. Phytother. Res. 23 (2009) 262-266
114. Tanabe T., Wada K., Okazaki T., and Numa S. Acetyl-coenzyme A carboxylase from rat liver. Subunit structure and proteolytic modification. Eur. J. Biochem. 57 (1975) 15-24
115. Gledhill J.R., Montgomery M.G., Leslie A.G., and Walker J.E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 13632-13637
116. Day P., Sharff A., Parra L., Cleasby A., Williams M., Horer S., Nar H., Redemann N., Tickle I., and Yon J. Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallogr. D Biol. Crystallogr. 63 (2007) 587-596
117. Scott J.W., van Denderen B.J., Jorgensen S.B., Honeyman J.E., Steinberg G.R., Oakhill J.S., Iseli T.J., Koay A., Gooley P.R., Stapleton D., and Kemp B.E. Thienopyridone drugs are selective activators of AMP-activated protein kinase beta1-containing complexes. Chem. Biol. 15 (2008) 1220-1230
118. Moreno D., Knecht E., Viollet B., and Sanz P. A769662, a novel activator of AMP-activated protein kinase, inhibits non-proteolytic components of the 26S proteasome by an AMPK-independent mechanism. FEBS Lett. 582 (2008) 2650-2654
119. Pang T., Zhang Z.S., Gu M., Qiu B.Y., Yu L.F., Cao P.R., Shao W., Su M.B., Li J.Y., Nan F.J., and Li J. Small molecule antagonizes autoinhibition and activates AMP-activated protein kinase in cells. J. Biol. Chem. 283 (2008) 16051-16060
120. Hemminki A. The molecular basis and clinical aspects of Peutz-Jeghers syndrome. Cell Mol. Life Sci. 55 (1999) 735-750
121. Shaw R.J. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. (Oxf) 196 (2009) 65-80
122. Inoki K., Zhu T., and Guan K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115 (2003) 577-590
123. Gwinn D.M., Shackelford D.B., Egan D.F., Mihaylova M.M., Mery A., Vasquez D.S., Turk B.E., and Shaw R.J. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30 (2008) 214-226
124. Shaw R.J., Bardeesy N., Manning B.D., Lopez L., Kosmatka M., DePinho R.A., and Cantley L.C. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6 (2004) 91-99
125. Tiainen M., Vaahtomeri K., Ylikorkala A., and Makela T.P. Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1). Hum. Mol. Genet. 11 (2002) 1497-1504
126. Imamura K., Ogura T., Kishimoto A., Kaminishi M., and Esumi H. 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 (2001) 562-567
127. Jones R.G., Plas D.R., Kubek S., Buzzai M., Mu J., Xu Y., Birnbaum M.J., and Thompson C.B. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18 (2005) 283-293
128. Fogarty S., and Hardie D.G. 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 (2009) 77-84
129. Budanov A.V., and Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 134 (2008) 451-460
130. Hippert M.M., O'Toole P.S., and Thorburn A. Autophagy in cancer: good, bad, or both?. Cancer Res. 66 (2006) 9349-9351
131. Hoyer-Hansen M., and Jaattela M. AMP-activated protein kinase: a universal regulator of autophagy?. Autophagy (2007) 3
132. Liang J., Shao S.H., Xu Z.X., Hennessy B., Ding Z., Larrea M., Kondo S., Dumont D.J., Gutterman J.U., Walker C.L., Slingerland J.M., and Mills G.B. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 9 (2007) 218-224
133. Partanen J.I., Nieminen A.I., and Klefstrom J. 3D view to tumor suppression: Lkb1, polarity and the arrest of oncogenic c-Myc. Cell Cycle 8 (2009) 716-724
134. Martin S.G., and St Johnston D. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature 421 (2003) 379-384
135. Baas A.F., Kuipers J., van der Wel N.N., Batlle E., Koerten H.K., Peters P.J., and Clevers H.C. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116 (2004) 457-466
136. Partanen J.I., Nieminen A.I., Makela T.P., and Klefstrom J. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 14694-14699
137. Lee J.H., Koh H., Kim M., Kim Y., Lee S.Y., Karess R.E., Lee S.H., Shong M., Kim J.M., Kim J., and Chung J. Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447 (2007) 1017-1020
138. Zhang L., Li J., Young L.H., and Caplan M.J. AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 17272-17277
139. Zheng B., and Cantley L.C. Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 819-822
140. Schneider M.B., Matsuzaki H., Haorah J., Ulrich A., Standop J., Ding X.Z., Adrian T.E., and Pour P.M. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120 (2001) 1263-1270
141. Anisimov V.N., Egormin P.A., Bershtein L.M., Zabezhinskii M.A., Piskunova T.S., Popovich I.G., and Semenchenko A.V. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull. Exp. Biol. Med. 139 (2005) 721-723
142. Anisimov V.N., Berstein L.M., Egormin P.A., Piskunova T.S., Popovich I.G., Zabezhinski M.A., Kovalenko I.G., Poroshina T.E., Semenchenko A.V., Provinciali M., Re F., and Franceschi C. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol. 40 (2005) 685-693
143. Evans J.M., Donnelly L.A., Emslie-Smith A.M., Alessi D.R., and Morris A.D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330 (2005) 1304-1305
144. Bowker S.L., Majumdar S.R., Veugelers P., and Johnson J.A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29 (2006) 254-258
145. Huang X., Wullschleger S., Shpiro N., McGuire V.A., Sakamoto K., Woods Y.L., McBurnie W., Fleming S., and Alessi D.R. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem. J. 412 (2008) 211-221
146. Goodwin P.J., Pritchard K.I., Ennis M., Clemons M., Graham M., and Fantus I.G. Insulin-lowering effects of metformin in women with early breast cancer. Clin. Breast Cancer 8 (2008) 501-505
147. McTiernan A. Mechanisms linking physical activity with cancer. Nat. Rev., Cancer 8 (2008) 205-211
148. Igata M., Motoshima H., Tsuruzoe K., Kojima K., Matsumura T., Kondo T., Taguchi T., Nakamaru K., Yano M., Kukidome D., Matsumoto K., Toyonaga T., Asano T., Nishikawa T., and Araki E. Adenosine monophosphate-activated protein kinase suppresses vascular smooth muscle cell proliferation through the inhibition of cell cycle progression. Circ. Res. 97 (2005) 837-844
149. Ben Sahra I., Laurent K., Loubat A., Giorgetti-Peraldi S., Colosetti P., Auberger P., Tanti J.F., Le Marchand-Brustel Y., and Bost F. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene 27 (2008) 3576-3586
150. Buzzai M., Jones R.G., Amaravadi R.K., Lum J.J., Deberardinis R.J., Zhao F., Viollet B., and Thompson C.B. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67 (2007) 6745-6752
151. Sanchez-Cespedes M., Parrella P., Esteller M., Nomoto S., Trink B., Engles J.M., Westra W.H., Herman J.G., and Sidransky D. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62 (2002) 3659-3662
152. Wingo S.N., Gallardo T.D., Akbay E.A., Liang M.C., Contreras C.M., Boren T., Shimamura T., Miller D.S., Sharpless N.E., Bardeesy N., Kwiatkowski D.J., Schorge J.O., Wong K.K., and Castrillon D.H. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4 (2009) e5137
153. Zheng B., Jeong J.H., Asara J.M., Yuan Y.Y., Granter S.R., Chin L., and Cantley L.C. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol. Cell 33 (2009) 237-247
154. Hadad S.M., Baker L., Quinlan P., Robertson K.E., Bray S.E., Thomson G., Kellock D., Jordan L.B., Purdie C.A., Hardie D.G., Fleming S., and Thompson A.M. Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer 9 (2009) 307
155. Andersson U., Treebak J.T., Nielsen J.N., Smith K.L., Abbott C.R., Small C.J., Carling D., and Richter E.A. Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity. Biochem. Biophys. Res. Commun. 329 (2005) 719-725
156. Leclerc I., Woltersdorf W.W., da Silva Xavier G., Rowe R.L., Cross S.E., Korbutt G.S., Rajotte R.V., Smith R., and Rutter G.A. Metformin, but not leptin, regulates AMP-activated protein kinase in pancreatic islets: impact on glucose-stimulated insulin secretion. Am. J. Physiol. Endocrinol. Metab. 286 (2004) E1023-E1031
157. Fonseca S.G., Burcin M., Gromada J., and Urano F. Endoplasmic reticulum stress in beta-cells and development of diabetes. Curr. Opin. Pharmacol. (2009)
158. Riboulet-Chavey A., Diraison F., Siew L.K., Wong F.S., and Rutter G.A. Inhibition of AMP-activated protein kinase protects pancreatic beta-cells from cytokine-mediated apoptosis and CD8+ T-cell-induced cytotoxicity. Diabetes 57 (2008) 415-423
159. Arad M., W B.D., Perez-Atayde A.R., McKenna W.J., Sparks E.A., Kanter R.J., McGarry K., Seidman J.G., and Seidman C.E. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J. Clin. Invest. 109 (2002) 357-362
160. Burwinkel B., Scott J.W., Buhrer C., van Landeghem F.K., Cox G.F., Wilson C.J., Hardie D.G., and Kilimann M.W. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the g2 subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am. J. Hum. Genet. 76 (2005) 1034-1049
161. Arad M., Seidman C.E., and Seidman J.G. AMP-activated protein kinase in the heart: role during health and disease. Circ. Res. 100 (2007) 474-488
162. Costford S.R., Kavaslar N., Ahituv N., Chaudhry S.N., Schackwitz W.S., Dent R., Pennacchio L.A., McPherson R., and Harper M.E. Gain-of-function R225W mutation in human AMPKgamma3 causing increased glycogen and decreased triglyceride in skeletal muscle. PLoS ONE 2 (2007) e903
163. Ouchi N., Shibata R., and Walsh K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle. Circ. Res. (2005)