VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans

Abstract

Objective: Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD) in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1) in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT) study.

Methods: 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance.

Results: In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%). In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002) while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001). Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10-11) but higher SLC2A1 expression (P = 0.009) in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes.

Conclusions: The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our data demonstrate that HFD induces a genetically determined and correlated decrease of GLUT1 and increase of VEGF which may affect memory performance.

Clinical trial registration number: NCT01631123.

Keywords: Cognition; GLUT1; High fat diet; VEGF.

Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Figures

Figure 1

VEGF levels are highly correlated in monozygous twins. Strong intrapair correlation of VEGF serum concentrations in (A) monozygous twins and no correlation in (B) dizygous twins. **p < 0.01.

Figure 2

VEGF levels increase in response to the 6-week HFD. VEGF serum concentrations at LF6, HF1 and HF6 (mean ± SEM; *p < 0.05, **p < 0.01). LF6, investigation day after 6 weeks of the low fat diet; HF1, investigation day after 1 week of the high fat diet; HF6, investigation day after 6 weeks of the high fat diet.

Figure 3

Reduced gene expression of VEGFA, KDR, and SLC2A1 in subcutaneous adipose tissue in response to HFD. Relative mRNA expression assessed by quantitative Real-Time PCR of (A)VEGFA, (B)KDR and (C)SLC2A1. Values are shown as mean ± SEM. *p < 0.05, ***p < 0.001. To compare the main effects a Repeated Measures ANOVA and Bonferroni adjusted posthoc test was used. LF6, investigation day after 6 weeks of the low fat diet; HF1, investigation day after 1 week of the high fat diet; HF6, investigation day after 6 weeks of the high fat diet.

Figure 4

SLC2A1 gene expression in AT differed between BMI categories.SLC2A1 gene expression in AT at LF6, HF1, and HF6 after stratification for BMI class (**p < 0.01). LF6, investigation day after 6 weeks of the low fat diet; HF1, investigation day after 1 week of the HFD; HF6, investigation day after 6 weeks of the HFD; AT, adipose tissue.

Figure 5

VEGF serum levels and SLC2A1 gene expression levels differed between rs9472159 genotypes. (A) VEGF serum concentrations at LF6, HF1, and HF6 after stratification for rs9472159 genotype and (B) change of VEGF serum concentrations (HF6-LF6) stratified for rs9472159 genotype. (C)SLC2A1 gene expression in AT after stratification rs9472159 genotype. *p < 0.05, **p < 0.01; LF6, investigation day after 6 weeks of the low fat diet; HF1, investigation day after 1 week of the HFD; HF6, investigation day after 6 weeks of the HFD.

Figure 6

Consolidation memory scores according to the Auditory Verbal Learning Task (A) before and after 6 weeks of HFD and (B) before and after HFD stratified by rs9472159 genotype. Consolidation memory score was defined as the number of correct words recalled after the fifth trial subtracted from the number of correct words recalled after 30 min delay, multiplied by −1 to create positive relations. Data are shown as mean ± SEM, *p < 0.05, **p < 0.01. LF6, investigation day after 6 weeks of the low fat diet; HF6, investigation day after 6 weeks of the HFD.