Systemic VEGF-A neutralization ameliorates diet-induced metabolic dysfunction.
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.
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, AustraliaLaboratory for Ageing Research, School of Medical Sciences, UNSW Australia, New South Wales, Australia.
Lindsay E
LE
Wu
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Christopher C
CC
Meoli
Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.
Salvatore P
SP
Mangiafico
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Daniel J
DJ
Fazakerley
Centre for Education and Research on Ageing and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, Concord, New South Wales, Australia.
Victoria C
VC
Cogger
Centre for Education and Research on Ageing and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, Concord, New South Wales, AustraliaFaculty of Pharmacy, Universiti Teknologi MARA, Bandar Puncak Alam, Selangor, Malaysia.
Mashani
M
Mohamad
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Himani
H
Pant
Laboratory for Ageing Research, School of Medical Sciences, UNSW Australia, New South Wales, Australia.
Myung-Jin
MJ
Kang
Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and The University of Sydney, Sydney, Australia.
Elizabeth
E
Powter
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
James G
JG
Burchfield
Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.
Chrysovalantou E
CE
Xirouchaki
Falls and Balance Research Group, Neuroscience Research Australia, Sydney, Australia.
A Stefanie
AS
Mikolaizak
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Jacqueline
J
Stöckli
Department of Biomedical Imaging, Genentech Inc., San Francisco, CA.
Ganesh
G
Kolumam
Department of Biomedical Imaging, Genentech Inc., San Francisco, CA.
Nicholas
N
van Bruggen
Centre for the Endothelium, Vascular Biology Program, Centenary Institute, and The University of Sydney, Sydney, Australia.
Jennifer R
JR
Gamble
Centre for Education and Research on Ageing and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, Concord, New South Wales, Australia.
David G
DG
Le Couteur
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
Gregory J
GJ
Cooney
Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia.
Sofianos
S
Andrikopoulos
Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, AustraliaCharles Perkins Centre, School of Molecular Bioscience, The University of Sydney, Sydney, Australia david.james@sydney.edu.au.
David E
DE
James
D050154:Adiposity / Q000502:physiology; D000821:Animal Feed / Q000032:analysis; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D004041:Dietary Fats; D007074:Immunoglobulin G; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D005947:Glucose