title: Dichotomous effects of VEGF-A on adipose tissue dysfunction.
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.
authors.affiliation: Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wernstedt Asterholm
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Bueno
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Brekken
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D052436:Adipose Tissue, White / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000473:pathology; D005355:Fibrosis; D005951:Glucose Tolerance Test; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D010641:Phenotype; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D004041:Dietary Fats; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2