Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders

Abstract

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.

Biglycan gene connects metabolic dysfunction with brain disorder

“…Animals were group housed (22–24 °C and 12 h light/dark cycle). At 3 months of age an initial body composition (NMR in a Bruker minispec series mq10 machine (Bruker BioSpin, Freemont, CA) and a baseline intraperitoneal glucose tolerance test (IPGTT) were performed as previously described [11]. The male mice were divided into groups of similar mass and body composition within genotype: wild type with regular drinking water, wild type with fructose (15% w/v) in the drinking water, Bgn 0/− with regular drinking water, and Bgn 0/− with fructose (15% w/v) in the drinking water.…”

“…Fructose appears to induce a stage of metabolic dysfunction in the brain, negatively impacting cognitive function [10]. Using systems nutrigenomics in a rodent model of high fructose consumption, we recently reported the biglycan gene ( Bgn ) as one of the key regulatory nodes in the hypothalamus (main brain center of metabolic control) networks affected by dietary fructose [11]. Mechanistic information about the role that Bgn plays in the metabolic action of fructose on brain is crucial to understand how diabetes and brain function are connected.…”

Similarities and interactions between the ageing process and high chronic intake of added sugars

“…In particular, as shown by Meng et al (165) , inflammation could mediate the damaging effects of fructose on cognition since inflammation is also increased in the brain following a HCIAS. Adolescent rats given a high-fructose maize syrup solution for 30 d developed neuro-inflammation with an increase in IL-6 and IL-1β protein levels in the hippocampus (172) .…”

“…The model induced metabolic alterations (dyslipidaemia and insulin resistance) and impaired memory, and was associated with very significant reprogramming of DNA methylation, transcript abundance, alternate splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signalling. Interestingly, DHA supplementation could largely reverse fructose-induced genomic and network modifications (165) . Many studies have highlighted an association between insulin sensitivity and cognitive function.…”

“…Recently, systems nutrigenomics was used to assess the effect of 6 weeks of 15 % fructose in drinking water on transcriptome and epigenome sequencing in rat hypothalamus (metabolic control) and hippocampus (cognitive processing) (165) . The model induced metabolic alterations (dyslipidaemia and insulin resistance) and impaired memory, and was associated with very significant reprogramming of DNA methylation, transcript abundance, alternate splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signalling.…”