title: Wnt-Lrp5 signaling regulates fatty acid metabolism in the osteoblast.
abstract: The Wnt coreceptors Lrp5 and Lrp6 are essential for normal postnatal bone accrual and osteoblast function. In this study, we identify a previously unrecognized skeletal function unique to Lrp5 that enables osteoblasts to oxidize fatty acids. Mice lacking the Lrp5 coreceptor specifically in osteoblasts and osteocytes exhibit the expected reductions in postnatal bone mass but also exhibit an increase in body fat with corresponding reductions in energy expenditure. Conversely, mice expressing a high bone mass mutant Lrp5 allele are leaner with reduced plasma triglyceride and free fatty acid levels. In this context, Wnt-initiated signals downstream of Lrp5, but not the closely related Lrp6 coreceptor, regulate the activation of β-catenin and thereby induce the expression of key enzymes required for fatty acid β-oxidation. These results suggest that Wnt-Lrp5 signaling regulates basic cellular activities beyond those associated with fate specification and differentiation in bone and that the skeleton influences global energy homeostasis via mechanisms independent of osteocalcin and glucose metabolism.
authors: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Julie L
authors: JL
authors: Frey
authors: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Zhu
authors: Z
authors: Li
authors: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Jessica M
authors: JM
authors: Ellis
authors: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Qian
authors: Q
authors: Zhang
authors: Center for Public Health Genomics, Departments of Medicine (Division of Cardiology) and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
authors: Charles R
authors: CR
authors: Farber
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Susan
authors: S
authors: Aja
authors: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Michael J
authors: MJ
authors: Wolfgang
authors: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA.
authors: Thomas L
authors: TL
authors: Clemens
authors: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Baltimore Veterans Administration Medical Center, Baltimore, Maryland, USA rriddle1@jhmi.edu.
authors: Ryan C
authors: RC
authors: Riddle
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin