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Activation of the AMP-activated protein kinase (AMPK) mediates adiponectin signalling to regulate glucose and lipid metabolism in muscle. However, the molecular mechanism by which adiponectin activates AMPK remains largely unknown. We have recently found that the BAR, PH, and PTB domain-containing adaptor protein APPL1 binds directly to the intracellular part of adiponectin receptors and mediates adiponectin-stimulated AMPK activation (Mao et al. (2006) Nat Cell Biol. 8,516-523). Here we report that APPL1 directly binds to LKB1, an upstream kinase of AMPK, via the BAR domain. Under basal condition, LKBI is localized predominantly in the nucleus of C2C12 cells. Treating cells with either adiponectin or metformin significantly stimulates LKB1 translocation to the cytosol. Overexpression of LKB1SL-26, a mutant form of LKB1 which maintains intact kinase activity but localizes exclusively in the nucleus, inhibited adiponectin and metformin-stimulated AMPK activation in C2C12 cells. The regulation of LKB1 translocation is dependent on phosphorylation at Ser307, which is mediated by protein kinase Cz (PKCz). Taken together, our results reveal a novel mechanism by which adiponectin and metformin stimulate LKB1 cytosolic translocation, which is essential for AMPK activation in muscle cells. ADA-Funded Research [ABSTRACT FROM AUTHOR]