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

Abstract

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, β-catenin, in the control of osteoblast metabolism. In vitro, Wnt ligands and agonists that stimulated β-catenin activation in osteoblasts enhanced fatty acid catabolism, whereas genetic ablation of β-catenin dramatically reduced oleate oxidation concomitant with reduced osteoblast maturation and increased glycolytic metabolism. Temporal ablation of β-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 β-oxidation are reduced in the skeleton of β-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.

The role of osteoblasts in energy homeostasis

“…Indeed, the expression of several enzymatic mediators of β-oxidation were decreased in Lrp5-deficient primary mouse osteoblasts and increased in primary osteoblasts that express a variant of Lrp5 (Lrp5 G171V ) associated with high bone mass or following Wnt10b stimulation 112 . Follow-up studies using mice with osteoblast-specific β-catenin-deficiency indicated that Wnt-signalling regulates fatty acid catabolism via the canonical Wnt-β-catenin pathway 168 . As Wnt-induced glycolysis was reported to be regulated by non-canonical mTOR activation and protein synthesis 138 , it seems that pathways downstream of Wnt signalling can differentially influence fuel utilization.…”

Lowering circulating apolipoprotein E levels improves aged bone fracture healing

“…Treatment with rApoE decreases glycolytic metabolism during osteoblast differentiation. Work in the bone field has identified an important role for cellular metabolism with respect to osteoblast differentiation (24)(25)(26)(27)(28)(29). Specifically, increased glycolytic metabolism is a prerequisite for robust osteoblast differentiation and mineralized matrix formation.…”

Dual Effects of Lipid Metabolism on Osteoblast Function

“…Subsequent genetic studies revealed that Wnt-mediated regulation of fatty acid oxidation proceeds via a β-catenin-dependent mechanism. Frey et al ( 95 ) found that only Wnt ligands that increase the abundance of β-catenin in cultured osteoblasts, increase the capacity to fully oxidize oleate to carbon dioxide. Since constitutive ablation of β-catenin in osteoblasts results in early lethality ( 96 ) in vivo , the generation of an inducible β-catenin knockout mouse (Ctnnb flox/flox ; Osteocalcin-CreER T2 ) was necessary to examine the transcription factor's effects on fatty acid oxidation.…”