Frey Julie L, Kim Soohyun P, Li Zhu, Wolfgang Michael J, Riddle Ryan C
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Endocrinology. 2018 Jan 1;159(1):272-284. doi: 10.1210/en.2017-00850.
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.
通过卷曲受体和低密度脂蛋白相关受体5共受体启动的Wnt信号传导在骨骼发育、稳态和修复过程中指导关键的合成代谢事件。最近的研究表明，Wnt信号传导还调节成骨细胞的中间代谢，诱导骨祖细胞中的葡萄糖消耗和成熟成骨细胞中的脂肪酸利用。在本研究中，我们研究了经典Wnt信号传导靶点β-连环蛋白在控制成骨细胞代谢中的作用。在体外，刺激成骨细胞中β-连环蛋白激活的Wnt配体和激动剂增强了脂肪酸分解代谢，而β-连环蛋白的基因敲除显著降低了油酸氧化，同时伴随着成骨细胞成熟的减少和糖酵解代谢的增加。体内成骨细胞中β-连环蛋白表达的时间性敲除产生了预期的低骨量表型，还导致白色脂肪组织质量增加、血脂异常和胰岛素敏感性受损。由于β-连环蛋白突变体骨骼中脂肪酸β-氧化的酶介质表达水平降低，这些结果进一步证实了成骨细胞在脂质代谢中的作用，并表明Wnt信号传导对脂肪酸利用的影响是通过其经典信号通路进行的。
