beta-Catenin Directs Long-Chain Fatty Acid Catabolism in the Osteoblasts of Male Mice

Wnt-initiated signaling through a frizzled receptor and the low-density lipoprotein-related receptor-5 coreceptor instructs key anabolic events during skeletal development, homeostasis, and repair. Recent studies indicate that Wnt signaling also regulates the intermediary metabolism of osteoblastic cells, inducing glucose consumption in osteoprogenitors and fatty acid utilization in mature osteoblasts. In this study, we examined the role of the canonical Wnt-signaling target, beta-catenin, in the control of osteoblast metabolism. In vitro, Wnt ligands and agonists that stimulated beta-catenin activation in osteoblasts enhanced fatty acid catabolism, whereas genetic ablation of beta-catenin dramatically reduced oleate oxidation concomitant with reduced osteoblast maturation and increased glycolytic metabolism. Temporal ablation of beta-catenin expression in osteoblasts in vivo produced the expected low-bone-mass phenotype and also led to an increase in white adipose tissue mass, dyslipidemia, and impaired insulin sensitivity. Because the expression levels of enzymatic mediators of fatty acid beta-oxidation are reduced in the skeleton of beta-catenin mutants, these results further confirm the role of the osteoblast in lipid metabolism and indicate that the influence of Wnt signaling on fatty acid utilization proceeds via its canonical signaling pathway.