Inhibition of soluble epoxide hydrolase is protective against the multiomic effects of a high glycemic diet on brain microvascular inflammation and cognitive dysfunction

Saivageethi Nuthikattu, Dragan Milenkovic, Jennifer E. Norman, John Rutledge, Amparo Villablanca

Research output: Contribution to journalArticlepeer-review

Abstract

Diet is a modifiable risk factor for cardiovascular disease (CVD) and dementia, yet relatively little is known about the effect of a high glycemic diet (HGD) on the brain’s microvasculature. The objective of our study was to determine the molecular effects of an HGD on hippocampal microvessels and cognitive function and determine if a soluble epoxide hydrolase (sEH) inhibitor (sEHI), known to be vasculoprotective and anti-inflammatory, modulates these effects. Wild type male mice were fed a low glycemic diet (LGD, 12% sucrose/weight) or an HGD (34% sucrose/weight) with/without the sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), for 12 weeks. Brain hippocampal microvascular gene expression was assessed by microarray and data analyzed using a multi-omic approach for differential expression of protein and non-protein-coding genes, gene networks, functional pathways, and transcription factors. Global hippocampal microvascular gene expression was fundamentally different for mice fed the HGD vs. the LGD. The HGD response was characterized by differential expression of 608 genes involved in cell signaling, neurodegeneration, metabolism, and cell adhesion/inflammation/oxidation effects reversible by t-AUCB and hence sEH inhibitor correlated with protection against Alzheimer’s dementia. Ours is the first study to demonstrate that high dietary glycemia contributes to brain hippocampal microvascular inflammation through sEH.

Original languageEnglish (US)
Article number3913
JournalNutrients
Volume13
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • Brain
  • Dementia
  • High glycemic diet
  • Maless
  • Microvascular
  • Multiomics
  • Soluble epoxide hydrolase inhibitor

ASJC Scopus subject areas

  • Food Science
  • Nutrition and Dietetics

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