title: Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms.
abstract: We have generated a novel monoclonal antibody targeting human FGFR1c (R1c mAb) that caused profound body weight and body fat loss in diet-induced obese mice due to decreased food intake (with energy expenditure unaltered), in turn improving glucose control. R1c mAb also caused weight loss in leptin-deficient ob/ob mice, leptin receptor-mutant db/db mice, and in mice lacking either the melanocortin 4 receptor or the melanin-concentrating hormone receptor 1. In addition, R1c mAb did not change hypothalamic mRNA expression levels of Agrp, Cart, Pomc, Npy, Crh, Mch, or Orexin, suggesting that R1c mAb could cause food intake inhibition and body weight loss via other mechanisms in the brain. Interestingly, peripherally administered R1c mAb accumulated in the median eminence, adjacent arcuate nucleus and in the circumventricular organs where it activated the early response gene c-Fos. As a plausible mechanism and coinciding with the initiation of food intake suppression, R1c mAb induced hypothalamic expression levels of the cytokines Monocyte chemoattractant protein 1 and 3 and ERK1/2 and p70 S6 kinase 1 activation.
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, Dept of Bioscience Diabetes, AstraZeneca, Mölndal, Sweden.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lelliott
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, Dept of Bioscience Diabetes, AstraZeneca, Mölndal, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ahnmark
authors.affiliation: Discovery Sciences Transgenics, AstraZeneca, Mölndal, Sweden.
authors.forename: Therese
authors.initials: T
authors.lastname: Admyre
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, Dept of Bioscience Diabetes, AstraZeneca, Mölndal, Sweden.
authors.forename: Ingela
authors.initials: I
authors.lastname: Ahlstedt
authors.affiliation: Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Irving
authors.affiliation: Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom.
authors.forename: Feenagh
authors.initials: F
authors.lastname: Keyes
authors.affiliation: Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, United States of America.
authors.forename: Laurel
authors.initials: L
authors.lastname: Patterson
authors.affiliation: Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, United States of America.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Mumphrey
authors.affiliation: Discovery Sciences Transgenics, AstraZeneca, Mölndal, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Bjursell
authors.affiliation: AstraZeneca, Discovery Sciences, Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Tracy
authors.initials: T
authors.lastname: Gorman
authors.affiliation: Discovery Sciences Transgenics, AstraZeneca, Mölndal, Sweden.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.affiliation: Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Buchanan
authors.affiliation: Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom.
authors.forename: Paula
authors.initials: P
authors.lastname: Harrison
authors.affiliation: Antibody Discovery and Protein Engineering, MedImmune, Cambridge, United Kingdom.
authors.forename: Tristan
authors.initials: T
authors.lastname: Vaughan
authors.affiliation: Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, United States of America.
authors.forename: Hans-Rudolf
authors.initials: HR
authors.lastname: Berthoud
authors.affiliation: Cardiovascular & Metabolic Disease Innovative Medicines, Dept of Bioscience Diabetes, AstraZeneca, Mölndal, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lindén
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D054410:Chemokine CCL7 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D066280:Circumventricular Organs / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism; D005260:Female; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020738:Leptin / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000235:genetics; D017481:Receptors, Somatostatin / Q000172:deficiency / Q000235:genetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D020738:Leptin; C574273:MC4R protein, mouse; C491209:Mchr1 protein, mouse; D044105:Receptor, Melanocortin, Type 4; D017481:Receptors, Somatostatin; D026362:Serum Response Factor; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases