Regulation of Osteoblast Metabolism by Wnt Signaling

Wnt/β-catenin signaling plays a critical role in the achievement of peak bone mass, affecting the commitment of mesenchymal pro-genitors to the osteoblast lineage and the anabolic capacity of osteoblasts depositing bone matrix. Recent studies suggest that this evolutionarily-conserved, developmental pathway exerts its anabolic effects in part by coordinating osteoblast activity with interme-diary metabolism. These findings are compatible with the cloning of the gene encoding the low-density lipoprotein related receptor-5 (LRP5) Wnt co-receptor from a diabetes-susceptibility locus and the now well-established linkage between Wnt signaling and me-tabolism. In this article, we provide an overview of the role of Wnt signaling in whole-body metabolism and review the literature re-garding the impact of Wnt signaling on the osteoblast's utilization of three different energy sources: fatty acids, glucose, and gluta-mine. Special attention is devoted to the net effect of nutrient utilization and the mode of regulation by Wnt signaling. Mechanistic studies indicate that the utilization of each substrate is governed by a unique mechanism of control with β-catenin-dependent signal-ing regulating fatty acid β-oxidation, while glucose and glutamine utilization are β-catenin-independent and downstream of mamma-lian target of rapamycin complex 2 (mTORC2) and mammalian target of rapamycin complex 1 (mTORC1) activation, respectively. The emergence of these data has provided a new context for the mechanisms by which Wnt signaling influences bone development.