Cargando…

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

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 genet...

Descripción completa

Detalles Bibliográficos
Autores principales: Schüler, Rita, Seebeck, Nicole, Osterhoff, Martin A., Witte, Veronica, Flöel, Agnes, Busjahn, Andreas, Jais, Alexander, Brüning, Jens C., Frahnow, Turid, Kabisch, Stefan, Pivovarova, Olga, Hornemann, Silke, Kruse, Michael, Pfeiffer, Andreas F.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001408/
https://www.ncbi.nlm.nih.gov/pubmed/29506909
http://dx.doi.org/10.1016/j.molmet.2018.02.004
_version_ 1783331992979374080
author Schüler, Rita
Seebeck, Nicole
Osterhoff, Martin A.
Witte, Veronica
Flöel, Agnes
Busjahn, Andreas
Jais, Alexander
Brüning, Jens C.
Frahnow, Turid
Kabisch, Stefan
Pivovarova, Olga
Hornemann, Silke
Kruse, Michael
Pfeiffer, Andreas F.H.
author_facet Schüler, Rita
Seebeck, Nicole
Osterhoff, Martin A.
Witte, Veronica
Flöel, Agnes
Busjahn, Andreas
Jais, Alexander
Brüning, Jens C.
Frahnow, Turid
Kabisch, Stefan
Pivovarova, Olga
Hornemann, Silke
Kruse, Michael
Pfeiffer, Andreas F.H.
author_sort Schüler, Rita
collection PubMed
description 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
format Online
Article
Text
id pubmed-6001408
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-60014082018-06-15 VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans Schüler, Rita Seebeck, Nicole Osterhoff, Martin A. Witte, Veronica Flöel, Agnes Busjahn, Andreas Jais, Alexander Brüning, Jens C. Frahnow, Turid Kabisch, Stefan Pivovarova, Olga Hornemann, Silke Kruse, Michael Pfeiffer, Andreas F.H. Mol Metab Original Article 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 Elsevier 2018-02-12 /pmc/articles/PMC6001408/ /pubmed/29506909 http://dx.doi.org/10.1016/j.molmet.2018.02.004 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Schüler, Rita
Seebeck, Nicole
Osterhoff, Martin A.
Witte, Veronica
Flöel, Agnes
Busjahn, Andreas
Jais, Alexander
Brüning, Jens C.
Frahnow, Turid
Kabisch, Stefan
Pivovarova, Olga
Hornemann, Silke
Kruse, Michael
Pfeiffer, Andreas F.H.
VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title_full VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title_fullStr VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title_full_unstemmed VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title_short VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans
title_sort vegf and glut1 are highly heritable, inversely correlated and affected by dietary fat intake: consequences for cognitive function in humans
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001408/
https://www.ncbi.nlm.nih.gov/pubmed/29506909
http://dx.doi.org/10.1016/j.molmet.2018.02.004
work_keys_str_mv AT schulerrita vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT seebecknicole vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT osterhoffmartina vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT witteveronica vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT floelagnes vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT busjahnandreas vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT jaisalexander vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT bruningjensc vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT frahnowturid vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT kabischstefan vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT pivovarovaolga vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT hornemannsilke vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT krusemichael vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans
AT pfeifferandreasfh vegfandglut1arehighlyheritableinverselycorrelatedandaffectedbydietaryfatintakeconsequencesforcognitivefunctioninhumans