It’s no secret that obesity, which plagues more than 600 million people worldwide—more than one in three adults in the U.S. alone—leads to serious health problems: cardiovascular disease, diabetes and even several types of cancer. But obesity has also been established as a risk factor for cognitive decline, particularly in middle-aged and older people.
What’s not as well understood is this link’s underlying molecular mechanism—and that’s exactly what a group of researchers at the University of Alabama at Birmingham sought to decipher in a four-part experiment on mice published last month in The Journal of Neuroscience.
First, the researchers studied behavior in healthy and obese mice during memory tasks involving object recognition and location. Much like previous research from other groups, the Alabama team found that compared with their healthy counterparts, the overweight mice performed poorly on a spatial memory task, which relies on the brain’s hippocampus.
Next, the researchers took a look at epigenetic differences in the hippocampi of healthy and obese mice—in other words, at whether environmental factors, in this case obesity, may have influenced the expression of genes in the hippocampus in either group of mice. Using a molecular purification technique to isolate for and analyze methylated DNA sequences (which are associated with gene suppression), the team confirmed that four genes associated with memory formation were not expressed as strongly in the obese mice—suggesting that their obesity had somehow influenced how cells “read” these genes. “One of the particularly exciting things is that this finding links two hot areas of neuroscience: epigenetic mechanisms and cognitive effects of obesity,” says David Sweatt, a neurobiologist at Alabama and study co-author.
One gene in particular, Sirtuin 1 (Sirt1), showed further epigenetic changes that were not observed in the other three genes. “This meant that Sirt1 could lie at the nexus of metabolic dysfunction and memory formation,” says lead author Frankie Heyward, a graduate student in Sweatt’s laboratory. “We were the first to explicitly implicate reduced Sirt1 and increased Sirt1 DNA methylation in the etiology of obesity-induced memory impairment.”
To test this theory, the researchers experimentally reduced the expression of Sirt1 in otherwise healthy mice and found that, just like obese mice, they performed poorly in the hippocampus-dependent memory task. Finally, to investigate possible treatment, they turned to resveratrol, a molecule that activates Sirt1. The team successfully demonstrated that obese mice whose diet was supplemented with resveratrol had enhanced memory, indistinguishable from that of the healthy mice. Heyward still has questions, though. “We didn’t look at our target genes in an unbiased manner,” he says. “We had particular a priori hypotheses and assumptions that focused on certain genes.” In the future he hopes to use recent innovations in RNA sequencing and other technologies to expand his study of gene dysregulation to the entire genome.
Terry Davidson, a neuroscientist at American University who was not involved with the study, says there is a need for further research into what the obesity-related causes of these epigenetic changes may be. “Is it a change in the blood–brain barrier that allows toxins to cross the barrier and get into the hippocampus?” he asks. “It could be a sequence of events that occur as part of a breakdown of our response to inflammation or something like that.” He notes that further analysis of these results could yield a better understanding of specific correlations between Sirt1 expression and body weight as well as how time and exposure may play detrimental roles.
And of course, the researchers wonder how accurately these behavioral models reflect what is happening in humans. Sirt1 is already being considered as a potential therapy for improving metabolic dysfunction and enhancing life span as well as for improving cognitive outcomes in older populations. Heyward believes that his findings provide motivation to design clinical trials geared toward determining whether targeting Sirt1 can also help salvage the memories of people who are obese. “And one other interesting question,” he adds, “is whether these alterations in gene expression and DNA methylation can be reversed or whether they’re permanent. That, at present, is unknown.”