Modulation of VEGF-B signaling by DDE exposure: effect on fatty acid accumulation

Introduction: Recently, it was demonstrated that vascular endothelial growth factor (VEGF)-B signaling, through an increase in the fatty acid transport protein (FATP) 3 and FATP4 expression can modulate the fatty acid uptake into organs such as adipose tissue (AT), liver and heart. (1) The p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE) is a persistent organic pollutant, that present endocrine disruptor properties. (2) It is present in blood circulation and is mainly accumulated in AT, leading to metabolic dysfunction and contributing to obesity. (3) Objective: To verify if p,p’-DDE exposure, in different diet contexts, can change VEGF-B signaling and thus modulate the uptake of fatty acid, across the endothelium, to different tissues. Methodology: Thirty 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 the expression of Vegfb, Vegfr1, Fatp3 and Fatp4 genes was quantified by qRT-PCR in mesenteric adipose tissue (mAT), liver and heart. Tissue lipid content was measured and plasma biochemical profile was analyzed. Statistical analysis included two-way ANOVA followed by Turkey’s multiple comparison test. Results: Rats fed with HFD and exposed to DDE manifested a more pronounced dyslipidemia and an increase in plasma markers of tissue dysfunction. However, HFD alone increased rats’ body, mAT and heart weight. In mAT, DDE exposure and HFD increased the expression of Vegfb, Vegfr1 and Fatp3 genes. Moreover, HFD increased in 157.39% the area of adipocytes and decreased in 54.66% the number of adipocytes per area of mAT. In liver, DDE exposure increased the expression of Vegfb, Vegfr1, Fatp3 and Fatp4 genes. Consequently, lipid content was higher in rats feed with HFD and exposed to DDE. In heart tissue, DDE exposure increased the expression of Vegfb, Vegfr1, Fatp3 and Fatp4 genes. Rats fed with HFD increased heart triglyceride concentration in 241.46%, compared to St diet group. Conclusion: The results obtained allowed to conclude that DDE exposure, in combination with HFD, promoted tissue dysfunction and dyslipidemia. DDE exposure modulated Vegfb/Vegfr1 signaling and thus the Fatp3 and Fatp4 genes, promoting fatty acid accumulation in several tissues. So, it is possible that DDE exposure can modulate fatty acid transport proteins and contribute to metabolic disorders and obesity.