LKB1 directly senses glycolytic metabolites to control AMPK activity

AMPK is phosphorylated and activated by LKB1 under low glucose conditions, but how the LKB1-AMPK axis senses glucose metabolism has been unclear. Here, we demonstrate that glycolytic metabolites (3-phosphoglycerate, 2-phosphoglycerate, and pyruvate) directly bind to and inhibit the LKB1 kinase complex. This interaction suppresses LKB1-dependent AMPK phosphorylation under high glucose conditions. LKB1 mutants that cannot bind these metabolites phosphorylate AMPK more effectively, and mice expressing these mutants are resistant to metabolic disorders induced by a high-fat diet. Furthermore, modulating PGK1 — the upstream enzyme that generates these metabolites — alters AMPK activation and metabolic phenotypes in mice. This work identifies LKB1 as a direct sensor of glucose metabolism.