Tencerova Michaela, Rendina-Ruedy Elizabeth, Neess Ditte, Færgeman Nils, Figeac Florence, Ali Dalia, Danielsen Morten, Haakonsson Anders, Rosen Clifford J, Kassem Moustapha
1Department of Molecular Endocrinology, University of Southern Denmark and Odense University Hospital, 5000 Odense, Denmark.
2Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074 USA.
Bone Res. 2019 Nov 14;7:35. doi: 10.1038/s41413-019-0076-5. eCollection 2019.
Enhanced bone marrow adipogenesis and impaired osteoblastogenesis have been observed in obesity, suggesting that the metabolic microenvironment regulates bone marrow adipocyte and osteoblast progenitor differentiation fate. To determine the molecular mechanisms, we studied two immortalized murine cell lines of adipocyte or osteoblast progenitors (BMSCs and BMSCs, respectively) under basal and adipogenic culture conditions. At baseline, BMSCs, and BMSCs exhibit a distinct metabolic program evidenced by the presence of specific global gene expression, cellular bioenergetics, and metabolomic signatures that are dependent on insulin signaling and glycolysis in BMSCs versus oxidative phosphorylation in BMSCs. To test the flexibility of the metabolic program, we treated BMSCs with parathyroid hormone, S961 (an inhibitor of insulin signaling) and oligomycin (an inhibitor of oxidative phosphorylation). The treatment induced significant changes in cellular bioenergetics that were associated with decreased adipocytic differentiation. Similarly, 12 weeks of a high-fat diet in mice led to the expansion of adipocyte progenitors, enhanced adipocyte differentiation and insulin signaling in cultured BMSCs. Our data demonstrate that BMSC progenitors possess a distinct metabolic program and are poised to respond to exogenous metabolic cues that regulate their differentiation fate.
在肥胖症中已观察到骨髓脂肪生成增强和成骨细胞生成受损，这表明代谢微环境调节骨髓脂肪细胞和成骨细胞祖细胞的分化命运。为了确定分子机制，我们在基础和成脂培养条件下研究了两种永生化的小鼠脂肪细胞或成骨细胞祖细胞系（分别为骨髓间充质干细胞和骨髓间充质干细胞）。在基线时，骨髓间充质干细胞和骨髓间充质干细胞表现出不同的代谢程序，这通过特定的全局基因表达、细胞生物能量学和代谢组学特征得以证明，这些特征在骨髓间充质干细胞中依赖于胰岛素信号传导和糖酵解，而在骨髓间充质干细胞中则依赖于氧化磷酸化。为了测试代谢程序的灵活性，我们用甲状旁腺激素、S961（一种胰岛素信号传导抑制剂）和寡霉素（一种氧化磷酸化抑制剂）处理骨髓间充质干细胞。该处理诱导了细胞生物能量学的显著变化，这些变化与脂肪细胞分化减少有关。同样，小鼠12周的高脂饮食导致脂肪细胞祖细胞扩增，增强了培养的骨髓间充质干细胞中的脂肪细胞分化和胰岛素信号传导。我们的数据表明，骨髓间充质干细胞祖细胞具有独特的代谢程序，并准备好对外源代谢信号作出反应，这些信号调节它们的分化命运。
