Journal
SCIENCE
Volume 310, Issue 5754, Pages 1642-1646Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1120781
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Funding
- NCI NIH HHS [CA84313, U01 CA084313] Funding Source: Medline
- NIGMS NIH HHS [R37 GM037828, R01 GM056203-09, GM056203, GM37828, R01 GM056203] Funding Source: Medline
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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.
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