Activation of AMPK by bitter melon triterpenoids involves CaMKKβ

Tristan J Iseli; Nigel Turner; Xiao-Yi Zeng; Gregory J Cooney; Edward W Kraegen; Sheng Yao; Yang Ye; David E James; Ji-Ming Ye

doi:10.1371/journal.pone.0062309

Activation of AMPK by bitter melon triterpenoids involves CaMKKβ

PLoS One. 2013 Apr 25;8(4):e62309. doi: 10.1371/journal.pone.0062309. Print 2013.

Authors

Tristan J Iseli¹, Nigel Turner, Xiao-Yi Zeng, Gregory J Cooney, Edward W Kraegen, Sheng Yao, Yang Ye, David E James, Ji-Ming Ye

Affiliation

¹ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases / metabolism*
Calcium / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism*
Enzyme Activation / drug effects
HeLa Cells
Humans
Hypoglycemic Agents / pharmacology*
Momordica charantia / chemistry*
Phosphorylation / drug effects
Protein Serine-Threonine Kinases / deficiency
Signal Transduction / drug effects
Terpenes / pharmacology*

Substances

Hypoglycemic Agents
Terpenes
Protein Serine-Threonine Kinases
STK11 protein, human
Calcium-Calmodulin-Dependent Protein Kinase Kinase
AMP-Activated Protein Kinase Kinases
AMP-Activated Protein Kinases
Calcium

Grants and funding

This work was supported by funding from a Project Grant [grant number 535930 to JMY and YY] of the National Health and Medical Research Council of Australia (NHMRC) and Australia-China Special Fund [grant number CH0812110 to DEJ, JMY and EWK]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.