Systemic VEGF-A Neutralization Ameliorates Diet-Induced Metabolic Dysfunction

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.

Metabolic regulation of adult stem cell-derived neurons

“…Both VEGF and IGF-1 have bi-directional links to metabolism. On one hand their expression is modulated by metabolic factors such as hypoxia, glucose metabolism and lipid metabolism, on the other hand, VEGF and IGF-1 signaling induce complex changes in cellular and systems metabolism (Arai et al, 2009;Broughton and Partridge, 2009;Kivelä et al, 2014;Kumar et al, 2014;Wu et al, 2014).…”

Battle of the Bulge

“…16 In this model, VEGF-A repression led to upregulation of VEGF-B and its downstream fatty acid transport proteins that control endothelial fatty acid uptake. 16,17 Most recently, Wu et al 18 demonstrated that VEGF-A-neutralizing monoclonal antibody administration in a high-fat diet-induced mouse model of obesity reversed insulin resistance, independent of changes in adiposity or insulin signaling. There are confounding issues on both sides that must be considered.…”

“…September 23, 2014 monoclonal antibody administration used by Wu et al 18 owing to the blockade of VEGF-A 165 b on the promotion of angiogenesis. As we continue to search for therapeutic interventions that target VEGF-A in obesity and related disorders, future studies must examine the effects on VEGF-A 165 b.…”

“…It would be informative to repeat these experiments by using alternative adipose-targeting Cre mouse models, such as the Retn-Cre mouse line. 19 In addition, intraperitoneal VEGF-neutralizing monoclonal antibody 18 selectively blocks extracellular VEGF effects but does not target intracellular pathways, and also has important effects on nonadipose tissue, specifically the liver. Although Wu et al 18 nicely showed that insulin sensitivity was improved, the effects on adipose tissue angiogenesis were not examined.…”

“…19 In addition, intraperitoneal VEGF-neutralizing monoclonal antibody 18 selectively blocks extracellular VEGF effects but does not target intracellular pathways, and also has important effects on nonadipose tissue, specifically the liver. Although Wu et al 18 nicely showed that insulin sensitivity was improved, the effects on adipose tissue angiogenesis were not examined. Therefore, whether VEGF-targeted therapies in obesity should aim for VEGF overexpression or for VEGF blockade remains unclear.…”