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      Dichotomous effects of VEGF-A on adipose tissue dysfunction.

      Proceedings of the National Academy of Sciences of the United States of America

      drug effects, Adipocytes, pathology, Adipose Tissue, White, blood supply, metabolism, physiopathology, Angiogenesis Inhibitors, pharmacology, Animals, Cell Hypoxia, Cell Size, Dietary Fats, Energy Metabolism, Fatty Liver, Fibrosis, Glucose Tolerance Test, Insulin Resistance, Mice, Mice, Inbred C57BL, Mice, Obese, Mice, Transgenic, Neovascularization, Physiologic, Organ Specificity, Phenotype, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Weight Gain

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          Abstract

          Obese fat pads are frequently undervascularized and hypoxic, leading to increased fibrosis, inflammation, and ultimately insulin resistance. We hypothesized that VEGF-A-induced stimulation of angiogenesis enables sustained and sufficient oxygen and nutrient exchange during fat mass expansion, thereby improving adipose tissue function. Using a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpression model, we demonstrate that the local up-regulation of VEGF-A in adipocytes improves vascularization and causes a "browning" of white adipose tissue (AT), with massive up-regulation of UCP1 and PGC1α. This is associated with an increase in energy expenditure and resistance to high fat diet-mediated metabolic insults. Similarly, inhibition of VEGF-A-induced activation of VEGFR2 during the early phase of high fat diet-induced weight gain, causes aggravated systemic insulin resistance. However, the same VEGF-A-VEGFR2 blockade in ob/ob mice leads to a reduced body-weight gain, an improvement in insulin sensitivity, a decrease in inflammatory factors, and increased incidence of adipocyte death. The consequences of modulation of angiogenic activity are therefore context dependent. Proangiogenic activity during adipose tissue expansion is beneficial, associated with potent protective effects on metabolism, whereas antiangiogenic action in the context of preexisting adipose tissue dysfunction leads to improvements in metabolism, an effect likely mediated by the ablation of dysfunctional proinflammatory adipocytes.

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          Author and article information

          Journal
          22451920
          3326476
          10.1073/pnas.1200447109

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