Mouse study suggests potential anorexia treatment

Anorexia nervosa, an eating disorder marked by intense fear of weight gain and often severe food restriction, is a serious and sometimes fatal condition. Although nonmedical treatments exist, there are no drugs currently approved to treat it.. However, researchers at Yale University have found that a small molecule, called Bobcat339, is effective in preventing mice from developing what they call activity-based anorexia in an established model for inducing the condition.

Bobcat339—named as a homage to the mascot for Bates College, where it was discovered—degrades a protein called TET3, Yale University researcher Yingqun Huang and her team reveal in a paper in the Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.2300015120). A member of the ten-eleven translocation (TET) family of proteins, TET3 regulates a group of neurons called AgRP neurons, Huang says. When activated, those neurons drive mice to eat. Reducing TET3 expression allows those neurons to be active, spurring mice to chow down. This TET3/AgRP pathway is predicted to be present in humans too, according to Huang.

“I’m excited to see that they found something that might work to mitigate some of the decreased feeding that we see in patients experiencing the disease,” says Ames Sutton Hickey, who studies the neurobiology of feeding behavior at Temple University.

Huang had initially set out to investigate the molecule as a diabetes treatment. She’d previously discovered that TET3’s expression was elevated in the livers of people with diabetes, and had learned that Bobcat339 was active against other TET family proteins. Huang decided to test it as a diabetes treatment in mice—and did not get the result she hoped for.

The mice began eating more, Huang says. “I was so disappointed!”

After some additional research, Huang and her team recognized TET3’s function in AgRP neurons. So she decided to test Bobcat339 in mice another time—this time, for anorexia rather than diabetes.

To induce activity-based anorexia in the rodents, researchers used an established model that involves removing all their food, returning it for only 2 h a day for 3 days. During this time, mice eat significantly less, lose weight, and exercise obsessively on a running wheel which they can access whenever they choose. After 3 days, the scientists return the food unrestricted, and revoke access to the running wheel for a recovery period of at least 1 week. Even after the researchers restore uninterrupted access to food and the mice regain their body weight, they still still show anxiety and depressive-like behaviors, Huang says.

In the study, the research team injected the mice with Bobcat339 right before food restriction began, as well as 7 and 14 days later. During the food restriction period, mice in the control group lost weight, while treated mice maintained theirs through the whole experiment. Treated mice also ate more than control group mice during the food restriction period, and demonstrated less wheel running activity in that time.

“I think we need to be very careful about how we interpret results that we’re performing in rodents,” Sutton Hickey says. “A mouse that is choosing to compulsively exercise instead of eating is a maladaptive response, and it could have translational relevance, but . . . we can’t say that these animals are experiencing anorexia nervosa, and I think we need to be very careful about how we frame that.”

Along a similar line, Huang says “it will be so much more complicated” in humans. She notes that people with anorexia may feel acute shame and anxiety around eating food. In addition to ramping up appetite, activated AgRP neurons also lessen anxiety and depression in mice, according to Huang. She imagines Bobcat339 could serve as a sort of one-two punch.

Next, the team will look to further understand more about how the compound works, as well as test its toxicity and consider its route of administration. Eventually, Huang says she’d like to develop it into a drug.