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PMID: 16308421 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.

Science (New York, N.Y.) ·Vol. 310 ·No. 5754 ·2005-12-09 ·Pages 1642-6

Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC

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 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha 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.

MeSH Terms
AMP-Activated Protein Kinases Animals Blood Glucose/analysis Diabetes Mellitus, Type 2/drug therapy,metabolism Enzyme Activation Female Gene Expression Regulation Gluconeogenesis/genetics Glucose/metabolism HeLa Cells Homeostasis Humans Hyperglycemia/drug therapy,metabolism Hypoglycemic Agents/pharmacology,therapeutic use Lipogenesis/genetics Liver/enzymology,metabolism Male Metformin/pharmacology,therapeutic use Mice Mice, Obese Multienzyme Complexes/metabolism Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Signal Transduction Trans-Activators/genetics,metabolism Transcription Factors
Chemicals
Blood Glucose Crtc2 protein, mouse Hypoglycemic Agents Multienzyme Complexes Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Trans-Activators Transcription Factors Metformin Protein Serine-Threonine Kinases Stk11 protein, mouse AMP-Activated Protein Kinases Glucose
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Shaw Reuben J
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. shaw@salk.edu
Lamia Katja A
Vasquez Debbie
Koo Seung-Hoi
Bardeesy Nabeel
Depinho Ronald A
Montminy Marc
Cantley Lewis C
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1120781
Email
shaw@salk.edu
Published
2005-12-09
Epub
2005-00-24
Pages
1642-6
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC3074427
Subset
IM
Grants
NIGMS NIH HHS · GM37828 · United States
NIGMS NIH HHS · R37 GM037828 · United States
NCI NIH HHS · U01 CA084313 · United States
NIGMS NIH HHS · GM056203 · United States
NCI NIH HHS · CA84313 · United States
NIGMS NIH HHS · R01 GM056203-09 · United States
NIGMS NIH HHS · R01 GM056203 · United States
External Links
PubMed source DOI: 10.1126/science.1120781 PMC Full Text View journal details
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