Antibody-Mediated Inhibition of the FGFR1c Isoform Induces a Catabolic Lean State in Siberian Hamsters

Abstract

Hypothalamic tanycytes are considered to function as sensors of peripheral metabolism. To facilitate this role, they express a wide range of receptors, including fibroblast growth factor receptor 1 (FGFR1). Using a monoclonal antibody (IMC-H7) that selectively antagonizes the FGFR1c isoform, we investigated possible actions of FGFR1c in a natural animal model of adiposity, the Siberian hamster. Infusion of IMC-H7 into the third ventricle suppressed appetite and increased energy expenditure. Likewise, peripheral treatment with IMC-H7 decreased appetite and body weight and increased energy expenditure and fat oxidation. A greater reduction in body weight and caloric intake was observed in response to IMC-H7 during the long-day fat state as compared to the short-day lean state. This enhanced response to IMC-H7 was also observed in calorically restricted hamsters maintained in long days, suggesting that it is the central photoperiodic state rather than the peripheral adiposity that determines the response to FGFR1c antagonism. Hypothalamic thyroid hormone availability is controlled by deiodinase enzymes (DIO2 and DIO3) expressed in tanycytes and is the key regulator of seasonal cycles of energy balance. Therefore, we determined the effect of IMC-H7 on hypothalamic expression of these deiodinase enzymes. The reductions in food intake and body weight were always associated with decreased expression of DIO2 in the hypothalamic ependymal cell layer containing tanycytes. These data provide further support for the notion the tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy intake and expenditure.

Tanycytes As Regulators of Seasonal Cycles in Neuroendocrine Function

“…It was previously shown that antibody-mediated targeting of the FGFR1c receptor reduced body weight, adiposity, and insulin resistance in animal models of obesity and type II diabetes (27–29). Subsequent in situ hybridization studies in the Siberian hamster revealed a high level expression of the FGFR1c in tanycytes, consistent with previous qPCR studies in the mouse (30, 31). Targeting of the FGFR1c in the long day (LD) obese Siberian hamster peripherally and centrally via intracerebroventicular infusion of a monoclonal FGFR1c antibody reduced food intake and body weight, which was associated with a decrease in expression of DIO2 in the ependymal cell layer containing tanycytes (31).…”

“…Subsequent in situ hybridization studies in the Siberian hamster revealed a high level expression of the FGFR1c in tanycytes, consistent with previous qPCR studies in the mouse (30, 31). Targeting of the FGFR1c in the long day (LD) obese Siberian hamster peripherally and centrally via intracerebroventicular infusion of a monoclonal FGFR1c antibody reduced food intake and body weight, which was associated with a decrease in expression of DIO2 in the ependymal cell layer containing tanycytes (31). This further supports the hypothesis that tanycytes are an important component of the mechanism by which the hypothalamus integrates central and peripheral signals to regulate energy homeostasis.…”

Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster

“…However, key downstream phosphorylation events are lost in the aged cohort in response to treatment. Previously we demonstrated that the actions of FGF21 mimetics were diminished in SD animals 21, 22 . However, results were equivocal as to whether this was a consequence of the central photoperiodic state or a result of reduced adiposity.…”

“…A monoclonal antibody targeting the hypothalamic FGFR1 causes potent hypophagia in rodents and non-human primates 22, 29 . The reduced food intake demonstrated in these studies is associated with reduced meal duration and frequency in young animals, suggesting a possible effect on satiety and/or reward.…”

“…Our work utilising a monoclonal antibody (IMC-H7), which targets FGFR1c, suggests that the photoperiodic state is important in determining the response 22 . However, the actions of FGF21 additionally require the presence of KLB, therefore our studies with IMC-H7 may not directly inform our understanding of the factors which determine FGF21 responsiveness 3 .…”