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The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Reuben J. Shaw,1,2*Katja A. Lamia,1,2Debbie Vasquez,2Seung-Hoi Koo,3,4Nabeel Bardeesy,5Ronald A. DePinho,6Marc Montminy,3Lewis C. Cantley1,2
The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threoninekinase, LKB1, which phosphorylates and activates AMPK [adenosinemonophosphate (AMP)–activated protein kinase]. The deletionof LKB1 in the liver of adult mice resulted in a nearly completeloss of AMPK activity. Loss of LKB1 function resulted in hyperglycemiawith increased gluconeogenic and lipogenic gene expression.In LKB1-deficient livers, TORC2, a transcriptional coactivatorof CREB (cAMP response element–binding protein), was dephosphorylatedand entered the nucleus, driving the expression of peroxisomeproliferator-activated receptor- coactivator 1 (PGC-1), whichin turn drives gluconeogenesis. Adenoviral small hairpin RNA(shRNA) for TORC2 reduced PGC-1 expression and normalized bloodglucose levels in mice with deleted liver LKB1, indicating thatTORC2 is a critical target of LKB1/AMPK signals in the regulationof gluconeogenesis. Finally, we show that metformin, one ofthe most widely prescribed type 2 diabetes therapeutics, requiresLKB1 in the liver to lower blood glucose levels.
1 Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. 2 Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. 3 Peptide Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. 4 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea. 5 Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. 6 Center for Applied Cancer Science and Department of Medical Oncology, Dana Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston, MA 02115, USA.
Present address: Molecular and Cell Biology Laboratories, TheSalk Institute, 10010 North Torrey Pines Road, La Jolla, CA92037–1002, USA.
* To whom correspondence should be addressed. E-mail: shaw{at}salk.edu
AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation.
K. A. Lamia, U. M. Sachdeva, L. DiTacchio, E. C. Williams, J. G. Alvarez, D. F. Egan, D. S. Vasquez, H. Juguilon, S. Panda, R. J. Shaw, et al. (2009)
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Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders.
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J. Physiol.
574, 41-53
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Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain.
Genetics and biology of pancreatic ductal adenocarcinoma..
A. F. Hezel, A. C. Kimmelman, B. Z. Stanger, N. Bardeesy, and R. A. DePinho (2006)
Genes & Dev.
20, 1218-1249
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Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPK{alpha}2 but not AMPK{alpha}1.
K. Sakamoto, E. Zarrinpashneh, G. R. Budas, A.-C. Pouleur, A. Dutta, A. R. Prescott, J.-L. Vanoverschelde, A. Ashworth, A. Jovanovic, D. R. Alessi, et al. (2006)
Am J Physiol Endocrinol Metab
290, E780-E788
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Glucose-induced repression of PPAR{alpha} gene expression in pancreatic {beta}-cells involves PP2A activation and AMPK inactivation..
K. Ravnskjaer, M. Boergesen, L. T Dalgaard, and S. Mandrup (2006)
J. Mol. Endocrinol.
36, 289-299
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coactivator 1
(PGC-1
Present address: Molecular and Cell Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037–1002, USA. 
