Modulation of VEGFB signaling by DDE exposure in obesity

Introduction: Obesity is a multifactorial disease characterized by an increase in adipose tissue (AT) mass, which should be accompanied by an increase in angiogenesis, modulated by vascular endothelial growth factor (VEGF)-A. Fatty acid uptake into AT, liver and heart was shown to be modulated by VEGF-B signaling, through an increase in fatty acid transport protein (FATP)3 and FATP4 expression. Persistent organic pollutants, as p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE), can accumulate in AT, leading to dysregulation of this tissue or, if released into blood circulation, can act as endocrine disruptors. The aim of this study was to verify if p,p’-DDE exposure, in different diet contexts, can change VEGF-B signalling and thus modulate the uptake of fatty acids across the endothelium into different tissues. It was also aimed to verify the effect of p,p’-DDE in the angiogenic process. Methods: Wistar rats were divided into four treatment groups during 12 weeks: Standard diet (St), St with DDE (St+DDE, 100 μg/kg/day), High-fat diet (HFD) and HFD with DDE (HFD+DDE, 100 μg/kg/day). At the end of the treatment, plasma biochemical analysis was performed and the effect in the uptake of fatty acids was analysed in mesenteric adipose tissue (mAT), liver and heart by analysing Vegfb, Vegfr1, Fatp3 and Fatp4 genes expression by qRT-PCR as well as by quantification of tissue lipid content. The angiogenic effect in mAT was evaluated by analysis of Vegfa and Vegfr2 gene expression by qRT-PCR and through the quantification of blood vessels present in tissue (immunohistochemistry to CD31). Statistical analysis included two-way ANOVA followed by Turkey´s multiple comparison test. Results: Although HFD alone increased rats’ body weight, mAT mass, adipocytes area and heart weight, rats concomitantly fed with HFD and exposed to DDE manifested a more pronounced dyslipidemia and an increase of plasma markers of tissue dysfunction. In mAT, HFD and DDE exposure promoted angiogenesis by increasing the expression of Vegfa and Vegfr2 genes, with DDE also increasing the release of VEGF-A. Moreover, DDE exposure and HFD increased the expression of Vegfb, Vegfr1 and Fatp3 genes, in mAT. In liver and heart, DDE exposure increased the expression of Vegfb, Vegfr1, Fatp3 and Fatp4 genes. In liver, HFD but also DDE showed to promote tissue lipid accumulation. In the heart, only rats fed with HFD increased heart triglyceride concentration. Conclusion: The results allowed to conclude that in animals fed an HFD, the exposure to DDE, promoted tissue dysfunction, dyslipidemia and angiogenesis. DDE exposure modulated Vegfb/Vegfr1 signaling and thus the Fatp3 and Fatp4 genes in several tissues, increasing lipid accumulation in the liver. Therefore, DDE exposure seems to contribute to metabolic disorders and obesity.