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Originally published in Science Express on 24 November 2005
Science 9 December 2005:
Vol. 310. no. 5754, pp. 1642 - 1646
DOI: 10.1126/science.1120781
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Research Articles

The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin

Reuben J. Shaw,1,2*{dagger} Katja A. Lamia,1,2 Debbie Vasquez,2 Seung-Hoi Koo,3,4 Nabeel Bardeesy,5 Ronald A. DePinho,6 Marc Montminy,3 Lewis C. Cantley1,2

The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)–activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element–binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-{gamma} coactivator 1{alpha} (PGC-1{alpha}), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1{alpha} expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 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.

{dagger} Present address: Molecular and Cell Biology Laboratories, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037–1002, USA.

* To whom correspondence should be addressed. E-mail: shaw{at}salk.edu

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   Abstract »    Full Text »    PDF »
Effects of Metformin on Microvascular Function and Exercise Tolerance in Women With Angina and Normal Coronary Arteries: A Randomized, Double-Blind, Placebo-Controlled Study.
S. Jadhav, W. Ferrell, I. A. Greer, J. R. Petrie, S. M. Cobbe, and N. Sattar (2006)
J. Am. Coll. Cardiol. 48, 956-963
   Abstract »    Full Text »    PDF »
Policosanol Inhibits Cholesterol Synthesis in Hepatoma Cells by Activation of AMP-Kinase.
D. K. Singh, L. Li, and T. D. Porter (2006)
J. Pharmacol. Exp. Ther. 318, 1020-1026
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase underpins hypoxic pulmonary vasoconstriction and carotid body excitation by hypoxia in mammals.
A. M. Evans (2006)
Exp Physiol 91, 821-827
   Abstract »    Full Text »    PDF »
SNF1-related kinases allow plants to tolerate herbivory by allocating carbon to roots.
J. Schwachtje, P. E. H. Minchin, S. Jahnke, J. T. van Dongen, U. Schittko, and I. T. Baldwin (2006)
PNAS 103, 12935-12940
   Abstract »    Full Text »    PDF »
Polyphenols Stimulate AMP-Activated Protein Kinase, Lower Lipids, and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor-Deficient Mice..
M. Zang, S. Xu, K. A. Maitland-Toolan, A. Zuccollo, X. Hou, B. Jiang, M. Wierzbicki, T. J. Verbeuren, and R. A. Cohen (2006)
Diabetes 55, 2180-2191
   Abstract »    Full Text »    PDF »
TORC1 and TORC2 Coactivators Are Required for Tax Activation of the Human T-Cell Leukemia Virus Type 1 Long Terminal Repeats.
Y.-T. Siu, K.-T. Chin, K.-L. Siu, E. Yee Wai Choy, K.-T. Jeang, and D.-Y. Jin (2006)
J. Virol. 80, 7052-7059
   Abstract »    Full Text »    PDF »
AMP-activated protein kinase - development of the energy sensor concept.
D. G. Hardie, S. A. Hawley, and J. W. Scott (2006)
J. Physiol. 574, 7-15
   Abstract »    Full Text »    PDF »
AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer.
H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki (2006)
J. Physiol. 574, 63-71
   Abstract »    Full Text »    PDF »
Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders.
B. Viollet, M. Foretz, B. Guigas, S. Horman, R. Dentin, L. Bertrand, L. Hue, and F. Andreelli (2006)
J. Physiol. 574, 41-53
   Abstract »    Full Text »    PDF »
Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain.
S. Ramamurthy and G. V. Ronnett (2006)
J. Physiol. 574, 85-93
   Abstract »    Full Text »    PDF »
AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues.
B. Xue and B. B. Kahn (2006)
J. Physiol. 574, 73-83
   Abstract »    Full Text »    PDF »
Emerging Biology of Malignant Salivary Gland Tumors Offers New Insights into the Classification and Treatment of Mucoepidermoid Cancer..
F. J. Kaye (2006)
Clin. Cancer Res. 12, 3878-3881
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AMP-activated protein kinase and the regulation of Ca2+ signalling in O2-sensing cells.
A. M. Evans (2006)
J. Physiol. 574, 113-123
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Endocrinology & Metabolism News, January 2006.
(2006)
J. Clin. Endocrinol. Metab. 91, 17a
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