Monoclonal antibody targeting of fibroblast growth factor receptor 1c ameliorates obesity and glucose intolerance via central mechanisms

PLoS One. 2014 Nov 26;9(11):e112109. doi: 10.1371/journal.pone.0112109. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Arcuate Nucleus of Hypothalamus / drug effects*
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Arcuate Nucleus of Hypothalamus / physiopathology
  • Chemokine CCL2 / agonists
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Chemokine CCL7 / agonists
  • Chemokine CCL7 / genetics
  • Chemokine CCL7 / metabolism
  • Circumventricular Organs / drug effects*
  • Circumventricular Organs / metabolism
  • Circumventricular Organs / physiopathology
  • Eating / drug effects
  • Energy Metabolism
  • Female
  • Gene Expression Regulation
  • Glucose Intolerance / drug therapy*
  • Glucose Intolerance / genetics
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / physiopathology
  • Humans
  • Hypothalamus / drug effects*
  • Hypothalamus / metabolism
  • Hypothalamus / physiopathology
  • Leptin / deficiency
  • Leptin / genetics
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Obesity / drug therapy*
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / physiopathology
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Melanocortin, Type 4 / deficiency
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptors, Somatostatin / deficiency
  • Receptors, Somatostatin / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / genetics
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Serum Response Factor / agonists
  • Serum Response Factor / genetics
  • Serum Response Factor / metabolism
  • Signal Transduction

Substances

  • Antibodies, Monoclonal
  • Chemokine CCL2
  • Chemokine CCL7
  • Leptin
  • MC4R protein, mouse
  • Mchr1 protein, mouse
  • Receptor, Melanocortin, Type 4
  • Receptors, Somatostatin
  • Serum Response Factor
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Mitogen-Activated Protein Kinases

Grants and funding

The study was funded by AstraZeneca and MedImmune. The funders provided support in the form of salaries for authors (all authors except L.P., M.B.M., and H-R.B) and a research grant for author H-R.B, but did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the “author contributions” section.