Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators.
5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA riboside) has been extensively used in vitro and in vivo to activate the AMP-activated protein kinase (AMPK), a metabolic sensor involved in both cellular and whole body energy homeostasis. However, it has been recently highlighted that AICA riboside also exerts AMPK-independent effects, mainly on AMP-regulated enzymes and mitochondrial oxidative phosphorylation (OXPHOS), leading to the conclusion that new compounds with reduced off target effects are needed to specifically activate AMPK. Here, we review recent findings on newly discovered AMPK activators, notably on A-769662, a nonnucleoside compound from the thienopyridone family. We also report that A-769662 is able to activate AMPK and stimulate glucose uptake in both L6 cells and primary myotubes derived from human satellite cells. In addition, A-769662 increases AMPK activity and phosphorylation of its main downstream targets in primary cultured rat hepatocytes but, by contrast with AICA riboside, does neither affect mitochondrial OXPHOS nor change cellular AMP:ATP ratio. We conclude that A-769662 could be one of the new promising chemical agents to activate AMPK with limited AMPK-independent side effects.
Guigas
Bruno
B
Hormone and Metabolic Research Unit, Université catholique de Louvain and de Duve Institute, Brussels, Belgium. b.guigas@lumc.nl
Sakamoto
Kei
K
Taleux
Nellie
N
Reyna
Sara M
SM
Musi
Nicolas
N
Viollet
Benoit
B
Hue
Louis
L
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D001713:Biphenyl Compounds; D020536:Enzyme Activators / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism*; D012263:Ribonucleosides / Q000378:metabolism; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism*
D001713:Biphenyl Compounds; D020536:Enzyme Activators; D011753:Pyrones; D012263:Ribonucleosides; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D055372:AMP-Activated Protein Kinases; D005947:Glucose; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
Annu Rev Pharmacol Toxicol. 2007;47:185-210
16879084
Biochem Biophys Res Commun. 2006 May 12;343(3):700-6
16563350
J Physiol. 2006 Jul 1;574(Pt 1):73-83
16709629
J Appl Physiol (1985). 2003 Sep;95(3):960-8
12777406
Biochem Pharmacol. 1996 Oct 11;52(7):999-1006
8831718
Diabetes. 2001 May;50(5):1076-82
11334411
FEBS Lett. 2002 Nov 6;531(2):189-92
12417310
Am J Physiol. 1997 Dec;273(6):E1107-12
9435525
J Biol Chem. 2007 Nov 9;282(45):32549-60
17855357
Endocrinology. 2005 Apr;146(4):1818-24
15665038
Cell Biochem Biophys. 2007;47(3):332-47
17652779
J Physiol. 2006 Jul 1;574(Pt 1):41-53
16644802
Cell Metab. 2006 Jun;3(6):403-16
16753576
Diabetes. 2005 Apr;54(4):928-34
15793229
J Biol Chem. 2005 Jul 1;280(26):25250-7
15878856
FASEB J. 1995 Apr;9(7):541-6
7737463
Curr Biol. 2002 Aug 20;12(16):1419-23
12194824
Eur J Biochem. 1995 Apr 15;229(2):558-65
7744080
Biochem Biophys Res Commun. 2004 Apr 9;316(3):853-8
15033479
J Biol Chem. 2002 Jul 5;277(27):23977-80
11997383
Diabetologia. 1996 Oct;39(10):1148-55
8897001
J Biol Chem. 2006 Nov 17;281(46):34870-9
16990266
Biochem Biophys Res Commun. 1994 May 16;200(3):1551-6
8185610
J Biol Chem. 2008 Jun 6;283(23):16051-60
18321858
Diabetes. 2002 Jul;51(7):2199-206
12086950
Hepatology. 2008 Feb;47(2):668-76
18098312
Cardiovasc Res. 1993 Jan;27(1):43-7
8458030
Biochem J. 2008 Jun 1;412(2):211-21
18387000
Front Biosci. 2008 Jan 01;13:3022-33
17981775
EMBO J. 2005 May 18;24(10):1810-20
15889149
Diabetes. 2004 Dec;53(12):3074-81
15561936
J Biol Chem. 2004 Mar 26;279(13):12076-80
14729664
J Biol Chem. 2006 Sep 8;281(36):25956-64
16816404
Diabetes. 2002 Oct;51(10):2886-94
12351423
Diabetes. 2007 Aug;56(8):2078-84
17513706
Diabetologia. 2001 Dec;44(12):2180-6
11793019
J Biol Chem. 2007 Feb 16;282(7):4516-4523
17179149
Front Biosci (Landmark Ed). 2009 Jan 01;14:19-44
19273052
Am J Physiol Regul Integr Comp Physiol. 2003 Apr;284(4):R936-44
12626360
Diabetes. 2006 Apr;55(4):865-74
16567505
Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E29-37
18477703
Diabetes. 2002 Jul;51(7):2074-81
12086935
Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85
17712357
Biochem J. 2007 Jun 15;404(3):499-507
17324122
Diabetes. 2006 Jul;55(7):2067-76
16804077
Biochem Biophys Res Commun. 2002 Jun 21;294(4):798-805
12061777
J Biol Chem. 2007 Nov 9;282(45):32539-48
17728241
Mol Cell. 2001 May;7(5):1085-94
11389854
Biochem J. 1992 Jan 1;281 ( Pt 1):267-72
1531010
Diabetes. 1991 Oct;40(10):1259-66
1657665
FEBS Lett. 1994 Oct 10;353(1):33-6
7926017
Cell. 2006 Feb 10;124(3):471-84
16469695