The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
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-γ coactivator 1α (PGC-1α), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1α 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.
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We thank M. Loda for the FAS antibody; J. Luo, A. Shaywitz, and O. Peroni for technical advice; K. Cichowski for help with the manuscript; D. Gwinn and C. Mealmaker for technical assistance; and the University of Iowa Gene Transfer Vector Core, supported in part by NIH and the Roy J. Carver Foundation, for adenoviral Cre preparations. This work was supported by grants GM056203, GM37828, and CA84313 from the NIH to L.C.C., M.M., and R.A.D., respectively. M.M. also was supported in part by the Hillblom Foundation.
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Science
Volume 310 | Issue 5754
9 December 2005
9 December 2005
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American Association for the Advancement of Science.
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Received: 30 September 2005
Accepted: 9 November 2005
Published in print: 9 December 2005
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