Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders

EBioMedicine. 2016 May:7:157-66. doi: 10.1016/j.ebiom.2016.04.008. Epub 2016 Apr 13.


Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient-host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine.

Keywords: Brain disorders; Brain networks; DHA; Epigenome; Extracellular matrix; Fructose; Metabolic diseases; Omega-3 fatty acid; Systems nutrigenomics; Transcriptome.

MeSH terms

  • Animals
  • Biglycan / genetics
  • Biglycan / metabolism
  • Cognition Disorders / genetics*
  • Epigenomics / methods
  • Fibromodulin / genetics
  • Fibromodulin / metabolism
  • Fructose / administration & dosage*
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks*
  • Hippocampus / chemistry
  • Humans
  • Hypothalamus / chemistry
  • Male
  • Metabolic Diseases / genetics*
  • Metabolic Networks and Pathways
  • Models, Animal
  • Nutrigenomics / methods*
  • Precision Medicine
  • Rats
  • Systems Biology / methods


  • Bgn protein, mouse
  • Biglycan
  • Fmod protein, mouse
  • Fibromodulin
  • Fructose