A monoclonal antibody targetting the FGFR‐1c isoform reduces body weight and food intake, which is, associated with a suppression of deiodinase 2 mRNA expression in hypothalamic tanycytes

Abstract

FGF21 plays a role in the peripheral regulation of energy balance, but its putative receptor (FGFR1c) is also expressed in tanycyte cells of the hypothalamus. The objective of the present study was to investigate the possible central actions of a monoclonal antibody (H7) that specifically targets FGFR1c in a natural model of adiposity, the Siberian hamster. Hypothalamic thyroid hormone availability, controlled by tanycytes, is the key regulator of seasonal cycles of body weight, so we aimed to determine the effect of H7 on local regulators of thyroid hormone availability: deiodinase enzymes DIO2 and DIO3. Hamsters maintained in their long day fat state (LD; n=12) or short day lean state (SD; n=12) were treated with H7 (n=6, 3 mg/kg, sc) or vehicle (n=6/photoperiod). This resulted in a significant reduction in food intake over the 72h treatment period in hamsters in LD (~60%), and a smaller reduction in food intake in SD (~40%). In LD, treatment with H7 resulted in a significant decrease (~50%) in DIO2 mRNA expression in the tanycyte layer of the medial basal hypothalamus. In SD, endogenous DIO2 expression was significantly lower than in LD as expected but H7 treatment did not significantly decrease its expression. In summary, a monoclonal antibody specifically targeting the FGFR1c isoform reduces food intake and body weight in a natural model of adiposity. These effects are far more substantial in hamster maintained in their LD fat state and appear to be associated with the reduction in mRNA expression of the deiodinase enzyme, DIO2.Supported by Eli Lilly and a BBSRC studentship.