Fructose in the diet can mean epigenomic reprogramming of the brain, changing the expression of hundreds of genes, including genes that may lead to a greater predisposition toward metabolic diseases such as diabetes, and brain disorders such as attention-deficit hyperactivity disorder. A link between fructose and the epigenome, report scientists based at the University of California, Los Angeles (UCLA), has emerged from an exercise in an emerging discipline called nutrigenomics.
Details appeared April 21 in the journal EBioMedicine, in an article entitled, “Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.” The article describes how fructose, a sugar that is common in the Western diet, promotes a cascade of epigenomic changes in the brain. This cascade, which seems to begin with DNA methylation changes to Bgn and Fmod, a pair of extracellular matrix genes, affects gene networks that govern cell metabolism, cell communication, inflammation, and neuronal signaling.
“We further demonstrate,” the article’s authors added, “that an omega-3 fatty acid, [docosahexaenoic acid, or DHA], reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders.”
To test the effects of fructose and DHA, the researchers trained rats to escape from a maze and then randomly divided the animals into three groups. For the next 6 weeks, one group of rats drank water with an amount of fructose that would be roughly equivalent to a person drinking a liter of soda per day. The second group was given fructose water and a diet rich in DHA. The third received water without fructose and no DHA.
After the 6 weeks, the rats were put through the maze again. The animals that had been given only the fructose navigated the maze about half as fast as the rats that drank only water—indicating that the fructose diet had impaired their memory. The rats that had been given fructose and DHA, however, showed very similar results to those that only drank water. This finding strongly suggests that the DHA eliminated fructose's harmful effects.
Other tests on the rats revealed more major differences: The rats receiving a high-fructose diet had much higher blood glucose, triglycerides, and insulin levels than the other two groups. Those results are significant because in humans elevated glucose, triglycerides, and insulin are linked to obesity, diabetes, and many other diseases.
The research team sequenced more than 20,000 genes in the rats' brains and identified more than 700 genes in the hypothalamus (the brain's major metabolic control center) and more than 200 genes in the hippocampus (which helps regulate learning and memory) that were altered by the fructose. The vast majority of the altered genes they identified are comparable to genes in humans. Among the conditions that can be caused by alterations to those genes are Parkinson's disease, depression, bipolar disorder, and other brain diseases.
The researchers also found that fructose disrupts gene expression by removing or adding a methyl group to the nucleotide cytosine. This type of modification plays a critical role in turning genes “on” or “off.”
“We found that fructose consumption induced a large-scale switch of the methylation patterns in both [the hypothalamus and the hippocampus]: 734 and 810 of differentially methylated loci (DMLs) showed hypomethylation and hypermethylation in hypothalamus, respectively; 972 and 900 DMLs showed hypomethylation and hypermethylation in hippocampus, respectively,” noted the authors. “DHA largely reversed the fructose-induced methylation changes in these two brain regions.”
“DHA changes not just one or two genes; it seems to push the entire gene pattern back to normal, which is remarkable,” said Xia Yang, a senior author of the study and a UCLA assistant professor of integrative biology and physiology. “And we can see why it has such a powerful effect.”
DHA occurs naturally in the membranes of our brain cells, but not in a large enough quantity to help fight diseases. “The brain and the body are deficient in the machinery to make DHA; it has to come through our diet,” added Fernando Gomez-Pinilla, a UCLA professor of neurosurgery and of integrative biology and physiology, and co-senior author of the paper.
“Food is like a pharmaceutical compound that affects the brain,” Gomez-Pinilla continued. He recommended avoiding sugary soft drinks, cutting down on desserts, and generally consuming less sugar and saturated fat.
Although DHA appears to be quite beneficial, Yang said it is not a magic bullet for curing diseases. Additional research will be needed to determine the extent of its ability to reverse damage to human genes. Such research could determine whether Bgn and Fmod are suitable targets for new drugs that could treat diseases stemming from disturbed gene-expression patterns in the brain.
“Our findings help explain the pathogenic actions of fructose on prevalent metabolic and brain disorders and provide proof-of-concept for nutritional remedies supported by nutrigenomics evidence,” the article’s authors concluded. “Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine.”