Description
YLF466D activated recombinant human α1β1γ1, α2β1γ1 and rat liver AMPK. It also activated AMPK α-subunit truncations containing an autoinhibitory domain(AID) and exhibited additivity with AMP and A-769662. Molecular docking of YLF466D with the S pombe AMPKa (25-351) suggests it may bind in the cleft between the kinase domain and the AID antagonizing the auto-inhibition distinct from AMP and A-769662. Incubation of YLF466D in Hela cells activated cellular AMPK without detectable changes in AMP:ATP ratio, proving AMPK was allosterically activated by YLF466D. YLF466D activated cellular AMPK in both L6 myotubes and HepG2 cells with evoking intracellular AMP:ATP ratio accompanied by depolarizing mitochondria membrane potential, but has no effect on the dephosphorylation of PP2Cα on AMPK. Thus, YLF466D activated cellular AMPK through dual mechanisms.
Functional studies shown YLF466D stimulated glucose uptake in L6 myotubes, decreased glucose output and lipid content in hepatocyte. Acute and chronic treatment of YLF466D on diabetic db/db mice and diet induced obese mice improved metabolic parameters