title: 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.
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK; Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Samms
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Jo E
authors.initials: JE
authors.lastname: Lewis
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Lory
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Maxine J
authors.initials: MJ
authors.lastname: Fowler
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Amy
authors.initials: A
authors.lastname: Warner
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Emmerson
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: School of Medicine, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Jeni C
authors.initials: JC
authors.lastname: Luckett
authors.affiliation: School of Medicine, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Perkins
authors.affiliation: Rowett Institute for Nutrition and Health, University of Aberdeen, Greenburn Road, Aberdeen AB21 9SB, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Wilson
authors.affiliation: Rowett Institute for Nutrition and Health, University of Aberdeen, Greenburn Road, Aberdeen AB21 9SB, UK.
authors.forename: Perry
authors.initials: P
authors.lastname: Barrett
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Kostas
authors.initials: K
authors.lastname: Tsintzas
authors.affiliation: School of Life Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. Electronic address: fran.ebling@nottingham.ac.uk.
authors.forename: Francis J P
authors.initials: FJ
authors.lastname: Ebling
mesh_terms: D050154:Adiposity / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000502:physiology; D006224:Cricetinae; D004435:Eating / Q000187:drug effects*; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D017111:Phodopus; D017440:Photoperiod; D020033:Protein Isoforms / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013851:Thinness / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D020033:Protein Isoforms; D013963:Thyroid Hormones; D051496:Receptor, Fibroblast Growth Factor, Type 1