Interactions between the gravitostat and the fibroblast growth factor system for the regulation of body weight.

Both fibroblast growth factors (FGFs), by binding to FGF receptors, and activation of the gravitostat, by artificial loading, decrease the body weight. Previous studies demonstrate that both the FGF system and loading have the capacity to regulate body weight independently of leptin. The aim of the present study was to determine the possible interactions between the effect of increased loading and the FGF system for the regulation of body weight. We observed that the body weight reducing effect of increased loading was abolished in mice treated with a monoclonal antibody directed against FGFR1c, suggesting interactions between the two systems. As serum levels of endocrine FGF21 and hepatic FGF21 mRNA were increased in the loaded mice compared to the control mice, we first evaluated the loading response in FGF21 over expressing mice with constant high FGF21 levels. Leptin treatment but not increased loading decreased the body weight in the FGF21 overexpressing mice, demonstrating that specifically the loading effect is attenuated in presence of high activity in the FGF system. However, as FGF21 KO mice displayed a normal loading response on body weight, FGF21 is neither mediating nor essential for the loading response. In conclusion, the body weight reducing effect of increased loading but not of leptin treatment is blocked by high activity in the FGF system. We propose that both the gravitostat and the FGF system regulate body weight independently of leptin and that pharmacologically enhanced activity in the FGF system reduces the sensitivity of the gravitostat.