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

Cell Metab. 2013 May 7;17(5):745-55. doi: 10.1016/j.cmet.2013.03.017. Epub 2013 Apr 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Animals
  • Bone and Bones / metabolism
  • Bone and Bones / physiology
  • Cell Differentiation / physiology
  • Cell Line
  • Glucose / metabolism
  • Glycolysis / physiology
  • HEK293 Cells
  • Humans
  • Lactic Acid / blood
  • Low Density Lipoprotein Receptor-Related Protein-5 / metabolism*
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Multiprotein Complexes / metabolism*
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteoblasts / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Wnt3A Protein / metabolism*
  • beta Catenin / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Low Density Lipoprotein Receptor-Related Protein-5
  • Multiprotein Complexes
  • Wnt3A Protein
  • beta Catenin
  • Lactic Acid
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • rac1 GTP-Binding Protein
  • Glucose