Anorexia nervosa has the highest mortality rate of any psychiatric disease, and as such, there is an urgent need to find therapeutic targets for this eating disorder. Now, researchers describe their new mouse model that shows how a combination of genetic and environmental risk factors can trigger the disease.
The team, from Columbia University Medical Center (CUMC), has published the results in the journal Translational Psychiatry.
They note that anorexia is the third most common chronic illness among young people in the US and has a mortality rate of 8-15%.
Many people with anorexia view themselves as being overweight, even when they are underweight, and they obsess about eating, food and weight control.
Symptoms of the eating disorder include very low body weight, food restriction, continuous pursuit of thinness, fear of weight gain and distorted body image. Additionally, some girls and women do not menstruate as a result of their low body weight.
Researchers have suspected that the risk of anorexia is raised by a combination of genetic, biological, psychological and sociocultural variables, but a major obstacle to the development of new treatments has been the lack of animal models that recap the pattern of disease onset in humans.
The researchers of this latest study, led by Lori Zeltser, PhD, from CUMC, say that although previous animal models of anorexia have included some variables, there were not any that were able to incorporate the social stress and genetic components of anxiety and anorexia that likely contribute to anorexia in humans.
Gene variant, social stress and restricted diet: a dangerous combination
As such, the team exposed adolescent mice to at least one copy of the BDNF gene variant. This gene has been linked with anorexia and anxiety in both mice and humans.
They then put the mice on a calorie-restricted diet, which the researchers say typically precedes anorexia in humans, working as a trigger for eating issues. The mice’s caloric intake was reduced by 20-30%, about the same equivalent to a typical human dieter’s caloric reduction.
“One driver of anorexia in humans is peer pressure, specifically the desire to be thin,” says Zeltser.
“People assumed that you couldn’t replicate that in a mouse,” she continues. “We decided to take peer pressure out of the equation and focus on social stress, which can be accomplished by housing mice alone, instead of in groups.”
When the adolescent mice with the BDNF gene variant were exposed to both social isolation stress and a restricted diet, the researchers observed that they were more likely to avoid eating than control mice.
Interestingly, when the researchers imposed these environmental variables on adult mice, the feeding behavior changes did not happen.
Additionally, when the team imposed either the social stress or reduced diet – but not both – on the adolescent mice with the gene mutation, the mice did not show much change in their feeding behavior.
Commenting on their findings, Zeltser says: “Our findings show that having the at-risk genotype alone is not sufficient to cause anorexia-like behavior, but it confers susceptibility to social stress and dieting, especially during adolescence. You need all of these variables in place to see this robust effect on eating.”
Model ‘closely replicates anorexic behavior in humans’
Because the study was conducted in mice and not humans, the researchers note that “there will always be questions about the extent to which a mouse model can fully capture a disorder as complex as [anorexia nervosa].”
However, they say that there are many key components of their model that “accurately reflect the conditions thought to promote eating disorders.” These include the interactions between early life stress and the BDNF variant, increasing susceptibility; dieting often precedes the onset of anorexia, and its peak incidence is in adolescence.
“In the end, we’ve achieved a model that closely replicates the factors that elicit anorexic behavior in humans,” concludes study author Moneek Madra, PhD, also from CUMC.
The researchers are presently using the new mouse model to investigate signaling pathways in the brain that may contribute to anorexic behavior. They hope to find therapeutic targets in the near future.
This article first appeared on ‘Medical News Today’ on 13 April 2016.