Activation of AMPK by Bitter Melon Triterpenoids Involves CaMKKβ |
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| Authors: | Tristan J Iseli Nigel Turner Xiao-Yi Zeng Gregory J Cooney Edward W Kraegen Sheng Yao Yang Ye David E James Ji-Ming Ye |
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| Institution: | 1. Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.; 2. Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Australia.; 3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; Virginia Commonwealth University, United States of America, |
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| 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 Ca2+-independent. We therefore propose that CaMKKβ is a key upstream kinase for BMT-induced activation of AMPK. |
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