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Science 310 (5754): 1642-1646

Copyright © 2005 by the American Association for the Advancement of Science

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

Abstract: 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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Role of KLF15 in Regulation of Hepatic Gluconeogenesis and Metformin Action.
M. Takashima, W. Ogawa, K. Hayashi, H. Inoue, S. Kinoshita, Y. Okamoto, H. Sakaue, Y. Wataoka, A. Emi, Y. Senga, et al. (2010)
Diabetes 59, 1608-1615
   Abstract »    Full Text »    PDF »
Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase.
J. Mankouri, P. R. Tedbury, S. Gretton, M. E. Hughes, S. D. C. Griffin, M. L. Dallas, K. A. Green, D. G. Hardie, C. Peers, and M. Harris (2010)
PNAS 107, 11549-11554
   Abstract »    Full Text »    PDF »
Metformin in Cancer Therapy: A New Perspective for an Old Antidiabetic Drug?.
I. Ben Sahra, Y. Le Marchand-Brustel, J.-F. Tanti, and F. Bost (2010)
Mol. Cancer Ther. 9, 1092-1099
   Abstract »    Full Text »    PDF »
Crosstalk between Insulin/Insulin-like Growth Factor-1 Receptors and G Protein-Coupled Receptor Signaling Systems: A Novel Target for the Antidiabetic Drug Metformin in Pancreatic Cancer.
E. Rozengurt, J. Sinnett-Smith, and K. Kisfalvi (2010)
Clin. Cancer Res. 16, 2505-2511
   Abstract »    Full Text »    PDF »
Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5.
P. W Caton, N. K Nayuni, J. Kieswich, N. Q Khan, M. M Yaqoob, and R. Corder (2010)
J. Endocrinol. 205, 97-106
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Potent and Specific Inhibition of mMate1-Mediated Efflux of Type I Organic Cations in the Liver and Kidney by Pyrimethamine.
S. Ito, H. Kusuhara, Y. Kuroiwa, C. Wu, Y. Moriyama, K. Inoue, T. Kondo, H. Yuasa, H. Nakayama, S. Horita, et al. (2010)
J. Pharmacol. Exp. Ther. 333, 341-350
   Abstract »    Full Text »    PDF »
AMPK and SIRT1: a long-standing partnership?.
N. B. Ruderman, X. Julia Xu, L. Nelson, J. M. Cacicedo, A. K. Saha, F. Lan, and Y. Ido (2010)
Am J Physiol Endocrinol Metab 298, E751-E760
   Abstract »    Full Text »    PDF »
AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-{beta} Peptide Metabolism.
V. Vingtdeux, L. Giliberto, H. Zhao, P. Chandakkar, Q. Wu, J. E. Simon, E. M. Janle, J. Lobo, M. G. Ferruzzi, P. Davies, et al. (2010)
J. Biol. Chem. 285, 9100-9113
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Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase.
C. Algire, L. Amrein, M. Zakikhani, L. Panasci, and M. Pollak (2010)
Endocr. Relat. Cancer 17, 351-360
   Abstract »    Full Text »    PDF »
Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity.
Y. Wang, H. Inoue, K. Ravnskjaer, K. Viste, N. Miller, Y. Liu, S. Hedrick, L. Vera, and M. Montminy (2010)
PNAS 107, 3087-3092
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Reduction of AMP-Activated Protein Kinase {alpha}2 Increases Endoplasmic Reticulum Stress and Atherosclerosis In Vivo.
Y. Dong, M. Zhang, B. Liang, Z. Xie, Z. Zhao, S. Asfa, H. C. Choi, and M.-H. Zou (2010)
Circulation 121, 792-803
   Abstract »    Full Text »    PDF »
AMPK as a mediator of hormonal signalling.
C. T. Lim, B. Kola, and M. Korbonits (2010)
J. Mol. Endocrinol. 44, 87-97
   Abstract »    Full Text »    PDF »
Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome.
E. Diamanti-Kandarakis, C. D Christakou, E. Kandaraki, and F. N Economou (2010)
Eur. J. Endocrinol. 162, 193-212
   Abstract »    Full Text »    PDF »
Isolation of Novel Animal Cell Lines Defective in Glycerolipid Biosynthesis Reveals Mutations in Glucose-6-phosphate Isomerase.
J. F. Haller, C. Smith, D. Liu, H. Zheng, K. Tornheim, G.-S. Han, G. M. Carman, and R. A. Zoeller (2010)
J. Biol. Chem. 285, 866-877
   Abstract »    Full Text »    PDF »
AMPK {beta}1 Deletion Reduces Appetite, Preventing Obesity and Hepatic Insulin Resistance.
N. Dzamko, B. J. W. van Denderen, A. L. Hevener, S. B. Jorgensen, J. Honeyman, S. Galic, Z.-P. Chen, M. J. Watt, D. J. Campbell, G. R. Steinberg, et al. (2010)
J. Biol. Chem. 285, 115-122
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Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction.
Y. Ikeda, K. Sato, D. R. Pimentel, F. Sam, R. J. Shaw, J. R. B. Dyck, and K. Walsh (2009)
J. Biol. Chem. 284, 35839-35849
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Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation.
E. Zeqiraj, B. M. Filippi, M. Deak, D. R. Alessi, and D. M. F. van Aalten (2009)
Science 326, 1707-1711
   Abstract »    Full Text »    PDF »
Central Administration of Resveratrol Improves Diet-Induced Diabetes.
G. Ramadori, L. Gautron, T. Fujikawa, C. R. Vianna, J. K. Elmquist, and R. Coppari (2009)
Endocrinology 150, 5326-5333
   Abstract »    Full Text »    PDF »
Mysterious Metformin.
C. R. Chong and B. A. Chabner (2009)
Oncologist 14, 1178-1181
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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)
Science 326, 437-440
   Abstract »    Full Text »    PDF »

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