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Mutation causes mice to behave as if they have an eating disorder

Cell Press

A genetic mutation associated with an increased risk of developing eating disorders in humans has now been found to cause several behavioral abnormalities in mice that are similar to those seen in people with anorexia nervosa. The findings, published online April 9 in Cell Reports, may point to novel treatments to reverse behavioral problems associated with disordered eating.

"It's been known for a long time that about 50% to 70% of the risk of getting an eating disorder was inherited, but the identity of the genes that mediate this risk is unknown," explains senior author Michael Lutter, MD, PhD, a neuroscientist at the University of Iowa's Carver College of Medicine.

In earlier studies, Lutter and his team sequenced the genomes of two large families with multiple members affected by eating disorders, and they found that family members with eating disorders often had rare mutations in the estrogen-related receptor alpha (ESRRA) gene or another gene that influences ESRRA's expression. Both mutations decreased the activity of the protein expressed by ESRRA. Although the protein is known to be expressed in the brain, relatively little is known about its function in neurons.

Through studies conducted in mice, the researchers now show that levels of ESRRA protein in the brain are regulated by energy reserves. Also, mice that were genetically bred to lack the protein exhibited obsessive-compulsive-like behaviors and social impairments, as well as a decreased willingness to work for high-fat food when hungry.

"This work identifies estrogen-related receptor alpha as one of the genes that is likely to contribute to the risk of getting anorexia nervosa or bulimia nervosa," Lutter says. "Clearly social factors--particularly the western ideal of thinness--contribute the remaining 'non-genetic' risk. We know that the rate of eating disorders has been increasing over the past several decades and this is likely due to social factors, not genetics."

Lutter and his colleagues now plan to study the mechanisms involved in estrogen-related receptor alpha's effects on the brain and to test whether novel treatments can reverse the behavioral problems seen in their mouse model.

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This work was supported by the National Institutes of Health, the Dylan Tauber Researcher Award from the Brain and Behavior Foundation, and the Klarman Family Foundation Grants Program in Eating Disorder Research.

Cell Reports, Cut et al.:"Behavioral Disturbances in Estrogen-Related Receptor Alpha-Null Mice" http://dx.doi.org/10.1016/j.celrep.2015.03.032

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