title: Activation of AMPK by bitter melon triterpenoids involves CaMKKβ.
abstract: We recently showed that bitter melon-derived triterpenoids (BMTs) activate AMPK and increase GLUT4 translocation to the plasma membrane in vitro, and improve glucose disposal in insulin resistant models in vivo. Here we interrogated the mechanism by which these novel compounds activate AMPK, a leading anti-diabetic drug target. BMTs did not activate AMPK directly in an allosteric manner as AMP or the Abbott compound (A-769662) does, nor did they activate AMPK by inhibiting cellular respiration like many commonly used anti-diabetic medications. BMTs increased AMPK activity in both L6 myotubes and LKB1-deficient HeLa cells by 20-35%. Incubation with the CaMKKβ inhibitor, STO-609, completely attenuated this effect suggesting a key role for CaMKKβ in this activation. Incubation of L6 myotubes with the calcium chelator EGTA-AM did not alter this activation suggesting that the BMT-dependent activation was Ca(2+)-independent. We therefore propose that CaMKKβ is a key upstream kinase for BMT-induced activation of AMPK.
authors: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.
authors: Tristan J
authors: TJ
authors: Iseli
authors: Nigel
authors: N
authors: Turner
authors: Xiao-Yi
authors: XY
authors: Zeng
authors: Gregory J
authors: GJ
authors: Cooney
authors: Edward W
authors: EW
authors: Kraegen
authors: Sheng
authors: S
authors: Yao
authors: Yang
authors: Y
authors: Ye
authors: David E
authors: DE
authors: James
authors: Ji-Ming
authors: JM
authors: Ye
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D029777:Momordica charantia / Q000737:chemistry*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D013729:Terpenes; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D002118:Calcium
references: Drugs Exp Clin Res. 1999;25(2-3):87-97
references: 10370869
references: Diabetes. 2008 May;57(5):1414-8
references: 18285556
references: Mol Endocrinol. 2000 Oct;14(10):1649-60
references: 11043579
references: J Nutr Biochem. 2011 Nov;22(11):1064-73
references: 21277185
references: Chem Biol. 2008 Nov 24;15(11):1220-30
references: 19022182
references: Cancer Res. 2007 Jul 15;67(14):6745-52
references: 17638885
references: Mol Cell Endocrinol. 2010 May 14;320(1-2):16-24
references: 20122988
references: Cell. 2008 May 2;133(3):462-74
references: 18455987
references: Diabetes. 2004 Jul;53(7):1649-54
references: 15220186
references: J Ethnopharmacol. 2011 Mar 24;134(2):422-8
references: 21211558
references: J Biol Chem. 2011 Aug 12;286(32):28066-79
references: 21669867
references: Biochem J. 2010 Jan 27;426(1):109-18
references: 19958286
references: Science. 2009 Dec 18;326(5960):1707-11
references: 19892943
references: J Toxicol Environ Health A. 2007 Jun;70(11):895-900
references: 17479403
references: Toxicol Appl Pharmacol. 2011 Nov 15;257(1):48-58
references: 21884717
references: Nature. 2001 Dec 13;414(6865):821-7
references: 11742415
references: Physiol Rev. 2009 Jul;89(3):1025-78
references: 19584320
references: J Biol Chem. 2008 Feb 22;283(8):4799-807
references: 18079111
references: Planta Med. 1990 Oct;56(5):426-9
references: 2077547
references: Trends Biochem Sci. 1999 Jun;24(6):232-6
references: 10366852
references: Am J Physiol Endocrinol Metab. 2008 Jan;294(1):E148-56
references: 17971514
references: Science. 2011 Jun 17;332(6036):1433-5
references: 21680840
references: Chem Biol. 2008 Mar;15(3):263-73
references: 18355726
references: J Clin Invest. 2004 Jan;113(2):274-84
references: 14722619
references: Biochem J. 1998 Aug 15;334 ( Pt 1):177-87
references: 9693118
references: J Med Food. 2010 Jun;13(3):520-7
references: 20521977
references: J Agric Food Chem. 2011 May 11;59(9):4553-61
references: 21456596
references: Cell Signal. 2011 Dec;23(12):2005-12
references: 21807092
references: Diabetes Res Clin Pract. 2010 Mar;87(3):293-301
references: 20171754
references: N Engl J Med. 2007 Jun 14;356(24):2457-71
references: 17517853
references: J Biol. 2003;2(4):28
references: 14511394
references: J Biol Chem. 2007 Nov 9;282(45):32549-60
references: 17855357
references: Diabetes Res Clin Pract. 2010 Jan;87(1):4-14
references: 19896746
references: J Biol Chem. 2005 Apr 8;280(14):13395-400
references: 15695819
references: J Biol Chem. 1998 Nov 27;273(48):31880-9
references: 9822657
references: Cell Metab. 2005 Jul;2(1):9-19
references: 16054095
references: Nature. 2011 Apr 14;472(7342):230-3
references: 21399626
references: Ann Intern Med. 2007 Sep 18;147(6):386-99
references: 17638715
references: PLoS One. 2012;7(7):e42115
references: 22860063
references: J Biol Chem. 2005 Aug 12;280(32):29060-6
references: 15980064
references: Biochem Soc Symp. 1999;64:13-27
references: 10207618
references: Exp Diabetes Res. 2011;2011:853501
references: 21754919
references: Cell Metab. 2006 Jun;3(6):403-16
references: 16753576
references: Cell Metab. 2005 Jul;2(1):21-33
references: 16054096
references: Nat Rev Cancer. 2007 May;7(5):357-69
references: 17446857
references: Diabetes. 2006 Aug;55(8):2256-64
references: 16873688