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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01343-14.

ACKNOWLEDGMENTS

We are indebted to Nadine Forbes-McBean in the Johns Hopkins University Phenotyping Core and Emily Farber in the University of Virginia Center for Public Health Genomics Genome Sciences Laboratory. Mouse models were kindly provided by Bart Williams and Gerard Karsenty.

This study was supported by NIH grants DK099134 to R.C.R., NS072241 to M.J.W., and a Merit Review Grant (BX001234) from the Veterans Administration to T.L.C. R.C.R. is the recipient of a Career Development Award (BX001284) from the Biomedical Laboratory Research and Development Service of the Veterans Administration Office of Research and Development. T.L.C. is the recipient of a Research Career Scientist Award from the Veterans Administration.