If you give a mouse an eating disorder, you might just figure out how to treat the disease in humans. In a new study published Thursday in Cell Press, researchers created mice who lacked a gene associated with disordered eating in humans. Without it, the mice showed behaviors not unlike those seen in humans with eating disorders: They tended to be obsessive compulsive and have trouble socializing, and they were less interested in eating high-fat food than the control mice. The findings could lead to novel drug treatments for some of the 24 million Americans estimated to suffer from eating disorders.
In a 2013 study, the same researchers went looking for genes that might contribute to the risk of an eating disorder. Anorexia nervosa and bulimia nervosa aren't straightforwardly inherited -- there's definitely more to an eating disorder than your genes -- but it does seem like some families might have higher risks than others. Sure enough, the study of two large families, each with several members who had eating disorders, yielded mutations in two interacting genes. In one family, the estrogen-related receptor α (ESRRA) gene was mutated. The other family had a mutation on another gene that seemed to affect how well ESRRA could do its job.
So in the latest study, they created mice that didn't have ESRRA in the parts of the brain associated with eating disorders.
"You can't go testing this kind of gene expression in a human," lead author and University of Iowa neuorscientist Michael Lutter said. "But in mice, you can manipulate the expression of the gene and then look at how it changes their behavior."
It's not a perfect analogy to what the gene mutation might do in a human, but the similarities can allow researchers to figure out the mechanism that causes the connection between your DNA and your eating habits.
The mice without ESRRA were tested for several eating-disorder-like behaviors: The researchers tested how hard they were willing to work for high fat food when they were hungry (less, it seemed, so much so that they weighed 15 percent less than their unaltered littermates), how compulsive they were, and how they behaved socially.
In general, the ESRRA-lacking mice were twitchier: They tended to overgroom, a common sign of anxiety in mice, and they were more wary of novelty, growing anxious when researchers put marbles into their cages. They also showed an inability to adapt: When researchers taught the mice how to exit a maze and then changed where the exit was, the mice without ESRRA spent way more time checking out the area where the exit should have been before looking for where it had gone.
The social changes were even more striking: Mice will usually show more interest in a new mouse than one they've met before, but in tests the modified mice showed the opposite preference, socializing with a familiar mouse when a new one was also presented.
They were also universally submissive to other mice, something the researchers detected with a sort of scientific game of chicken. Two mice are placed at either end of a tube, and one always plows past the other to get to the opposite side. It's just the way mice size each other up -- someone has to be on top. But every single one of the modified mice let themselves get pushed around.
"100% of the mice lacking this gene were subordinate," Lutter said. "I've never seen an experiment before that produced a 0% verses 100% result."
The avoidance of fats has an obvious connection to human disorders. But the social anxiety and rigidity are also close analogies to disordered eating in humans.
Now that Lutter and his colleagues know that the gene does something similar in mice, they can start looking for the actual mechanism that's tripping these switches in the brain. They know that the gene's pathway is very important for energy metabolism, especially in the breakdown of glucose. It's possible that mutations in the gene cause some kind of impairment in neurons' ability to get and process energy, but they can't be sure yet.
They'll see if they can pinpoint affected neurons and fix them. They're also going to test some drugs that are known to affect this gene and its pathways. It's possible that they'll land on a treatment that helps calm these negative behaviors in affected mice, leading to treatments for humans with the mutation.
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