Anorexia nervosa is a serious mental illness that can be dangerous to health. The causes are not fully understood, and treatment options are limited. Yale researchers have discovered a promising new therapeutic for anorexia nervosa. They have identified a small-molecule degrader of TET3, which led to significant improvements in food intake and overall health in an animal model. This discovery offers hope for developing a much-needed new treatment for anorexia nervosa.
Researchers at Yale discovered that a small synthetic molecule called Bobcat339 initially thought to be a good molecule for treating type 2 diabetes, can inhibit TET3. This protein regulates feeding and mood via Agouti-related protien (AgRP) neurons in the brain. When tested on mice, Bobcat339 led to hyperphagia and anti-anxiety and anti-depressive effects. These results have led researchers to investigate its potential use in treating anorexia nervosa.
“In humans, [anorexia nervosa] usually manifests during puberty, but mood problems often persist through adulthood. A similar thing happened with our mouse model,” said Yingqun Huang, MD, PhD
Anorexia nervosa is characterized by reduced food intake, low body weight, and mood disorders like depression and anxiety. Treatment with current interventions such as psychotherapy and nutritional support is difficult. Yale researchers used an activity-based anorexia model in mice to induce anorexia behavior. They found that administering Bobcat339 led to higher food intake and lower compulsive behavior during the restrictive period. Additionally, mice administered with Bobcat339 did not exhibit depressive or anxious behaviors after resuming normal feeding.
“In humans, anorexia (AN) usually manifests during puberty, but mood problems often persist through adulthood. A similar thing happened with our mouse model,” says Huang. In contrast, mice treated with Bobcat339 showed fewer of these behaviors.
“This small molecule helps mice maintain their food intake, maintain their body weight, and inhibit compulsive behaviors,” she says. “This drug is also working in mitigating anxious and depressive-like behaviors.”
The team’s discovery of the synthetic molecule Bobcat339 as a potential therapeutic for anorexia nervosa could also have the potential for treating mood disorders. Unlike typical antidepressants that take weeks, Bobcat339 improved mood problems in mice in as little as a day. The team hopes to conduct further studies to evaluate its ability to treat cancer-induced anorexia and depression in the future.
The study titled “A small-molecule degrader of TET3 as a treatment for anorexia nervosa in an animal model” was conducted by researchers at Yale School of Medicine. The research aimed to find a potential therapeutic for anorexia nervosa using a small synthetic molecule, Bobcat339, a TET3 protein inhibitor.
To conduct the study, the researchers used a well-established activity-based anorexia model in mice. In this model, the mice were kept in an apparatus with a running wheel, and their food intake was restricted to only two hours per day for three days. This induced anorexia behavior in the mice, causing them to reduce their food intake, lose body weight, and exhibit obsessive-compulsive wheel-running behavior. After three days, the researchers resumed regular feeding.
The team administered Bobcat339 to the mice via intraperitoneal injections and monitored their food intake and compulsive wheel running during the restrictive and recovery periods. The researchers also observed the effect of Bobcat339 on anxiety- and depressive-like behaviors using the open field and forced swim tests. The team also conducted experiments to study the mechanism of action of Bobcat339. They used Clustered, regularly interspaced short palindromic repeats (CRISPR) knockdown of TET3, specifically in AgRP neurons in mice, to observe the effects on hyperphagia and anti-anxiety and anti-depressive effects.
Data were analyzed using statistical methods, and the results were presented as means ± SEM (scanning electron microscope). The significance of the results was determined using one-way or two-way ANOVA (Analysis of Variance), followed by post hoc tests.
In conclusion, the study utilized an established animal model and various behavioral tests to evaluate the effects of Bobcat339 on anorexia nervosa and associated mood disorders. The results were analyzed using statistical methods, and the mechanism of action was studied using CRISPR knockdown.
Further research is needed to determine the safety and efficacy of the TET3 degrader in human clinical trials. However, these initial findings offer hope for developing a much-needed new treatment for anorexia nervosa.
Journal Reference:
- Haining Lv, Jonatas Catarino, Da Li, and Yingqun Huang, A small-molecule degrader of TET3 as a treatment for anorexia nervosa in an animal model. PNAS. DOI: 10.1073/pnas.2300015120