Systemic vascular endothelial growth factor-A (VEGF-A) neutralization ameliorates diet induced metabolic dysfunction
- Lindsay E. Wu1,2,*,
- Christopher C. Meoli1,*,
- Salvatore P. Mangiafico3,
- Daniel J. Fazakerley1,
- Victoria C. Cogger4,
- Mashani Mohamad4,5,
- Himani Pant1,
- Myung-Jin Kang2,
- Elizabeth Powter6,
- James G. Burchfield1,
- Chrysovalantou E. Xirouchaki3,
- A. Stefanie Mikolaizak7,
- Jacqueline Stöckli1,
- Ganesh Kolumam8,
- Nicholas van Bruggen8,
- Jennifer R. Gamble6,
- David Le Couteur4,
- Gregory J. Cooney1,
- Sofianos Andrikopoulos3 and
- David E. James1,9,#
- 1Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria Rd Darlinghurst, NSW 2010 Australia
- 2Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales NSW 2052 Australia
- 3Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria 3084, Australia
- 4Centre for Education and Research on Ageing and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, Building 18 Concord Hospital, Hospital Rd, Concord NSW 2139 Australia.
- 5Faculty of Pharmacy, Universiti Teknologi MARA, Bandar Puncak Alam Selangor, Malaysia
- 6Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and The University of Sydney, Sydney, Australia
- 7Falls and Balance Research Group, Neuroscience Research Australia
- 8Department of Biomedical Imaging, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
- 9Charles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia
- #Corresponding Author: David E. James,
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 present study, we sought to identify the effects of vascular endothelial growth factor A (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 signalling. 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.
* These authors contributed equally to this work.
- Received October 28, 2013.
- Accepted March 25, 2014.
- © 2014 by the American Diabetes Association.
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