Therefore we investigated the acute and delayed response of

Therefore, we investigated the acute and delayed response of 92 human mono- and dizygous twins to an acute shift from low fat to high fat diet with respect to serum levels of VEGF and the expression of SLC2A1 in subcutaneous adipose tissue (AT). By comparing the degree of concordance of basal and diet induced responses within and between monozygous vs. dizygous twin pairs, we could determine the heritability of these responses. Moreover, we tested cognitive performance using a sensitive memory task previously shown to be modulated by dietary restriction [10], [11] before and at the end of the high fat diet and assessed its association with VEGF and GLUT1.
Material and methods
Results
Discussion Stimulated by studies linking cognitive function to the dietary regulation of GLUT1 and its regulation by VEGF, we investigated the translatability of these findings into humans. Our data confirm an inverse link between the expression of GLUT1 and serum levels of VEGF through their regulation by food intake. In addition, we report extensive heritability of the expression of both factors and identified a genetic variant partially explaining the heritability. Moreover, this variant was linked to cognitive functions, which again concurs with the data from mice and provides possible links for the well-established role of high fat diet and in particular high saturated fat for the risk of developing dementia [16], [17], [18], [19]. GLUT1 shows the highest expression in the blood trans-isomer barrier and the brain requires GLUT1 for adequate function [6], [20], [21], [22]. Earlier studies demonstrated an upregulation of GLUT1 expression and glucose transport upon treatment with VEGF in rat brain cortical endothelia and in retinal endothelial cells [23], [24] as well as in bovine aortic endothelial cells in which VEGF strongly upregulated glucose transport via GLUT1 while GLUT4 was unaffected [25]. The upregulation of GLUT1 by VEGF therefore was shown in several vascular tissues across different species. Adipocytes primarily express GLUT4 while GLUT1 shows a low level of expression and is not regulated by insulin or glucose [21]. Adipose tissue biopsies contain endothelial cells, macrophages, and preadipocytes, which account for about 50% of the cells present. We therefore tested whether GLUT1 is regulated by VEGF in primary human adipocytes and did not observe any regulation, suggesting that the changes might be related to other cell types present in the biopsies. An additional aspect was introduced by the extensive heritability of VEGF, which was the highest among several cytokines analyzed in our twin study including IL6 and TNFα, which showed no or a very modest heritability. A certain heritability of VEGF had been shown in family studies [26]. Our heritability estimates for VEGF are considerably higher since we chose twins without significant differences in body weight and standardized dietary intakes and thereby corrected for the significant environmental alterations of VEGF levels. This raises the possibility that the impact of VEGF may differ substantially in humans depending on the inherited level of expression. A potentially helpful finding in our NUGAT study was that the rs9472159 polymorphism was associated with levels of VEGF and GLUT1. Being located in an enhancer- and promoter-associated histone mark region, it was assumed to potentially alter expression of surrounding genes, like VEGFA [15]. The additional association with GLUT1 concurs with the well-established regulation of GLUT1 by VEGF providing one possible explanation for the association. This genetic polymorphism should facilitate further studies on the role of VEGF and GLUT1 since this information is readily available in many human studies. Although Hardy–Weinberg equilibrium was not present in our sample, previous studies assessed its association with serum VEGF [9] suggesting that our sample was only slightly unbalanced. However, the role of this polymorphism certainly needs to be viewed with caution since earlier studies have shown the modest reproducibility of genetic associations derived from relatively small studies.