Fig. 1Wnt signaling regulates the utilization of three fuel substrates by cells of the osteoblast lineage. Activation of Wnt signaling via the interaction of a Wnt ligand with a frizzled receptor (Fzd) and the low-density lipoprotein related receptor-5 (Lrp5) co-receptor inactivates the destruction complex consisting of disheveled (Dvl), Axin, glycogen synthase kinase-3β (Gsk3β), adenomatous polyposis coli (Apc), and casein kinase-1 (Ck-1). In mature osteoblasts, this allows the accumulation of β-catenin and its translocation to the nucleus, where the transcription factor activates the expression of genes involved in mitochondrial long-chain fatty acid oxidation. In osteoprogenitors, Wnt signaling activates mammalian target of rapamycin complex 1 (mTORC1) and mammalian target of rapamycin complex 2 (mTORC2) signaling to increase glutaminolysis and glycolysis, respectively. Wnt ligand binding inhibits Gsk3β activity and its ability to activate the tuberous sclerosis 1/2 (Tsc1/Tsc2) complex that inhibits mTORC1 activity. Activation of mTORC1 increases the abundance of glutaminase, the first enzyme in glutaminolysis. Activation of the mTORC2 complex, which regulates the abundance of proteins involved in glycolysis, is downstream of Rac family small GTPase 1 (Rac1). By inhibiting the entry of glucose into the tricarboxylic acid (TCA) cycle, Wnt regulates the availability of substrates for histone acetyltransferases. Red lines represent interactions that are suppressed by the activation of Wnt signaling, while green lines indicate interactions that are enhanced. mLST8, mammalian lethal with SEC13 protein 8; Sin1, stress activated protein kinase interacting protein 1.