WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation

WNT signaling controls many biological processes including cell differentiation in metazoans. However, how WNT reprograms cell identity is not well understood. We have investigated the potential role of cellular metabolism in WNT-induced osteoblast differentiation. WNT3A induces aerobic glycolysis known as Warburg effect by increasing the level of key glycolytic enzymes. The metabolic regulation requires LRP5 but not β-catenin and is mediated by mTORC2-AKT signaling downstream of RAC1. Suppressing WNT3A-induced metabolic enzymes impairs osteoblast differentiation in vitro. Deletion of Lrp5 in the mouse, which decreases postnatal bone mass, reduces mTORC2 activity and glycolytic enzymes in bone cells and lowers serum lactate levels. Conversely, mice expressing a mutant Lrp5 that causes high bone mass exhibit increased glycolysis in bone. Thus, WNT-LRP5 signaling promotes bone formation in part through direct reprogramming of glucose metabolism. Moreover, regulation of cellular metabolism may represent a general mechanism contributing to the wide-ranging functions of WNT proteins.