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Dichotomous effects of VEGF-A on adipose tissue dysfunction
- Source :
- Proceedings of the National Academy of Sciences. 109:5874-5879
- Publication Year :
- 2012
- Publisher :
- Proceedings of the National Academy of Sciences, 2012.
-
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.
- Subjects :
- Vascular Endothelial Growth Factor A
medicine.medical_specialty
Adipose Tissue, White
Adipose tissue macrophages
Mice, Obese
Neovascularization, Physiologic
Adipose tissue
Angiogenesis Inhibitors
Mice, Transgenic
030209 endocrinology & metabolism
Inflammation
White adipose tissue
Biology
Weight Gain
Proinflammatory cytokine
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Insulin resistance
Fibrosis
Adipocyte
Internal medicine
Adipocytes
medicine
Animals
Cell Size
030304 developmental biology
0303 health sciences
Multidisciplinary
Glucose Tolerance Test
Biological Sciences
medicine.disease
Dietary Fats
Vascular Endothelial Growth Factor Receptor-2
Cell Hypoxia
Fatty Liver
Mice, Inbred C57BL
Phenotype
Endocrinology
chemistry
Organ Specificity
Insulin Resistance
medicine.symptom
Energy Metabolism
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....232b77378fbf6c402e83deeb7f584820