Systemic VEGF-A Neutralization Ameliorates Diet-Induced Metabolic Dysfunction

  1. David E. James1,9
  1. 1Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  2. 2Laboratory for Ageing Research, School of Medical Sciences, UNSW Australia, New South Wales, Australia
  3. 3Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
  4. 4Centre for Education and Research on Ageing and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, Concord, New South Wales, Australia
  5. 5Faculty of Pharmacy, Universiti Teknologi MARA, Bandar Puncak Alam, Selangor, Malaysia
  6. 6Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and The University of Sydney, Sydney, Australia
  7. 7Falls and Balance Research Group, Neuroscience Research Australia, Sydney, Australia
  8. 8Department of Biomedical Imaging, Genentech Inc., San Francisco, CA
  9. 9Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia
  1. Corresponding author: David E. James, david.james{at}sydney.edu.au.
  1. L.E.W. and C.C.M. contributed equally to this work.

Abstract

The vascular endothelial growth factor (VEGF) family of cytokines are important regulators of angiogenesis that have emerged as important targets for the treatment of obesity. While serum VEGF levels rise during obesity, recent studies using genetic models provide conflicting evidence as to whether VEGF prevents or accelerates metabolic dysfunction during obesity. In the current study, we sought to identify the effects of VEGF-A neutralization on parameters of glucose metabolism and insulin action in a dietary mouse model of obesity. Within only 72 h of administration of the VEGF-A–neutralizing monoclonal antibody B.20-4.1, we observed almost complete reversal of high-fat diet–induced insulin resistance principally due to improved insulin sensitivity in the liver and in adipose tissue. These effects were independent of changes in whole-body adiposity or insulin signaling. These findings show an important and unexpected role for VEGF in liver insulin resistance, opening up a potentially novel therapeutic avenue for obesity-related metabolic disease.

Footnotes

  • Received October 28, 2013.
  • Accepted March 27, 2014.
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  1. Diabetes vol. 63 no. 8 2656-2667
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