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Mouse Study Uncovers Diet-Related Changes in Stress Gene Expression and Epigenetics

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A new study in mice hints that dieting is linked to alterations in stress hormone patterns — including prolonged gene expression and epigenetic changes — that may lead to binge eating and cravings for high fat foods once a diet is done.

A University of Pennsylvania research team reported online today in the Journal of Neuroscience that curbing caloric intake over several weeks or restricting fat intake led to elevated levels of stress hormones in mice, as well as changes in the expression and methylation of stress-related genes in a specific region of the mouse brain. Those involved in the study say the findings highlight the link between stress and food cravings — hinting that successful weight management strategies may hinge, in part, on controlling stress.

"These results suggest that dieting not only increases stress, making successful dieting more difficult, but that it may actually 'reprogram' how the brain responds to future stress and emotional drives for food," senior author Tracy Bale, director of the University of Pennsylvania's Neuroscience Center, said in a statement.

Despite the health risks associated with being overweight or obese, the researchers explained, diets are notoriously difficult to maintain over long periods of time and many individuals regain weight lost through calorie restriction.

For their part, Bale and her co-workers speculated that such yo-yo diet patterns might be related to stress and stress-related hormones, which have been previously linked to a propensity to indulge in calorie-dense foods.

"The elevated weight regain and increased risk for diabetes and related metabolic disease after dieting make identification of novel therapeutic targets critical," the team wrote. "Current treatments predominantly focus on appetite reduction, although less is known regarding the central mechanisms contributing to treatment resistance and failure, especially that of the involvement of stress pathways."

To begin exploring potential ties to dieting lapses and stress, the researchers compared control mice fed a normal diet with calorically restricted mice that received three-quarters of the typical chow intake over three weeks. Mice in the calorically restricted group lost between 10 and 15 percent body weight on the diet, researchers reported, while mice in the control group gained weight.

When they stressed mice from both groups by restraining them for 15 minutes, the team found that mice from the caloric restricted group took longer to recover from the external stress, showing higher levels of the stress hormone corticosterone both before and after being exposed to stressors in the lab.

Under longer-term, chronic stress, they added, all mice were prone to "binge eating" —consuming more than half of their daily calories in the span of an hour. But mice that had previously been calorie restricted diet ate more calories — especially calories from high fat foods — under these conditions.

Using a TaqMan real-time PCR approach, the team found that mice in the caloric restriction group showed decreased expression of a gene coding for a stress-related hormone called corticotropin releasing factor in a region of the brain known as the bed nucleus of the stria terminalis.

Moreover, they explained, bisulfite sequencing of the CRF promoter region revealed a decline in CFR promoter methylation in the same brain area, even after calorically restricted mice returned to a normal diet.

Similar CRF expression and methylation patterns also appeared in mice that were exposed to — and then taken off of — a high-fat diet, the team noted, suggesting that "increased stress sensitivity may be a common component regardless of the method used to lose weight."

Meanwhile, when the control and formerly calorie restricted animals were presented with high-fat food options, the team detected enhanced expression of genes coding for two so-called orexigenic hormones — melanin-concentration hormone and orexin — in mice that had been on the lower calorie diet.

These hormones appear to contribute to food craving and binges, the researchers explained, since an MCH receptor antagonizing drug made post-diet mice less likely to consume excessive calories when high-fat foods were made available to them again.

"Together these results suggest that the stress associated with moderate caloric restriction promotes long-term alterations in genes critical in feeding and reward circuitry that influence food intake and stress-related behaviors," the team noted.

"These changes may in part be driven by epigenetic mechanisms," they added, explaining that epigenetic alterations "likely hold an evolutionary advantage in times of famine, but in our current environment of high caloric availability would function against our health and contribute to difficulty in weight management."

While the researchers conceded that more research is needed to see if the same patterns hold in humans, they argue that the results are consistent with the notion that managing stress may help individuals control food cravings over time.

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