Fos-induced osteosarcoma growth causes a cachexia-like phenotype in mice and correlates with high Fgf21 serum levels

The dimeric AP-1 transcription factor has been described as a regulator of bone metabolism, but also of adipocyte biology. More specifically, its family members adopt specific functions in the regulation of adipocyte differentiation and adipose tissue hypoxia, but also in controlling lipolysis, energy expenditure and insulin sensitivity. In this study, we analyzed the role of the AP-1 family member Fos, whose ubiquitous over-expression in transgenic mice has been described to cause osteosarcoma formation, on adipose tissue, glucose and lipid metabolism. More specifically, we analyzed the metabolic phenotype of the respective mouse model by histological analyses, monitoring gene expression, determination of serum parameters and ex vivo adipogenesis assays. We show that FosTg mice additionally display an age-dependent loss of white adipose tissue, which is associated with reduced adipocyte size. Quantitative real-time PCR analyses of white adipose tissue as well as in vitro studies using adipocyte-derived stromal cells excluded a cell-autonomous defect in adipocyte differentiation. However, FosTg mice displayed low circulating glucose levels along with increased glucose tolerance and insulin sensitivity. By proteomic analysis we identified elevated serum levels of fibroblast growth factor 21 (Fgf21) in FosTg mice which could explain the observed reduced hepatic lipogenesis and white adipose tissue mass. Most importantly, we demonstrated that this metabolic phenotype is dependent on osteosarcoma formation by crossing the FosTg mice with mice deficient for Rsk2, a kinase necessary for tumor growth. Moreover, we could show a direct correlation between tumor burden and Fgf21 serum levels in our mouse model. In summary, our data identify Fgf21 as a potential regulator of glucose and lipid metabolism in Fos transgenic osteosarcoma-bearing mice, thereby supporting its essential function in the regulation of the metabolic phenotype associated with cancer cachexia.