title: WNT-LRP5 signaling induces Warburg effect through mTORC2 activation during osteoblast differentiation.
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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Emel
authors.initials: E
authors.lastname: Esen
authors.forename: Jianquan
authors.initials: J
authors.lastname: Chen
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Karner
authors.forename: Adewole L
authors.initials: AL
authors.lastname: Okunade
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Patterson
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D019344:Lactic Acid / Q000097:blood; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D060509:Wnt3A Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; D046912:Multiprotein Complexes; D060509:Wnt3A Protein; D051176:beta Catenin; D019344:Lactic Acid; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D005947:Glucose