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

TLDR

LKB1, a tumor‑suppressor kinase, activates AMPK by phosphorylation. The study demonstrates that metformin lowers blood glucose in the liver only when LKB1 is present. In LKB1‑deficient livers, dephosphorylated TORC2 translocates to the nucleus, upregulates PGC‑1α, and stimulates gluconeogenesis. Deletion of LKB1 abolishes hepatic AMPK activity, causes hyperglycemia with increased gluconeogenic and lipogenic gene expression, and TORC2‑mediated PGC‑1α activation drives this phenotype, as shRNA knockdown of TORC2 restores glucose levels.

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.