Metabolic programming determines the lineage-differentiation fate of murine bone marrow stromal progenitor cells

Abstract

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^adipo and BMSCs^osteo, respectively) under basal and adipogenic culture conditions. At baseline, BMSCs^adipo, and BMSCs^osteo 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^osteo versus oxidative phosphorylation in BMSCs^adipo. To test the flexibility of the metabolic program, we treated BMSCs^adipo 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.

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Funding

Odense Universitetshospital (Odense University Hospital)(R29-A1374)

Danish Diabetes Academy supported by the Novo Nordisk foundation