A New Drug Rescues Mice from Anorexia by Boosting Hunger-Driving Neuropeptides AgRP and NPY | Research

The takeaway

The small molecule Bobcat339 degraded the enzyme TET3 in hypothalamic neurons, boosting production of appetite-driving neuropeptides AgRP and NPY, which increased feeding, reduced compulsive exercise, and prevented death in a mouse model of anorexia nervosa.

Reduced ABA lethality
Bobcat339 prevented death in the activity-based anorexia mouse model by boosting AgRP and NPY neuropeptide production, increasing food intake, and reducing compulsive exercise

What the researchers found

Bobcat339 induced TET3 protein degradation specifically in hypothalamic AgRP neurons, leading to:

- **Increased neuropeptide expression**: Upregulation of AgRP (agouti-related peptide), NPY (neuropeptide Y), and VGAT (vesicular GABA transporter) — all drivers of feeding behavior.

- **Behavioral rescue in ABA model**: Increased food intake, decreased compulsive running wheel activity, and reduced lethality in the activity-based anorexia mouse model.

- **Conserved mechanism**: Bobcat339 stimulated AgRP, NPY, and VGAT expression in a TET3-dependent manner in both mouse and human neuronal cells, suggesting cross-species relevance.

- **Anxiolytic effects**: The treatment also reduced anxiety/depressive-like behaviors.

Why it matters

Anorexia nervosa kills more people than any other psychiatric disorder, and there are currently no FDA-approved drugs for it. This study identifies a druggable molecular target (TET3) that controls the brain's most powerful hunger-driving neuropeptides. By activating the AgRP/NPY system — which directly drives feeding — Bobcat339 addresses the core biological dysfunction in anorexia rather than just managing symptoms.

How the study worked

The study used the well-established activity-based anorexia (ABA) mouse model, which combines food restriction with voluntary running wheel access — mice develop paradoxical hyperactivity and self-starvation mimicking human anorexia nervosa. Bobcat339 was administered to ABA mice, and outcomes included food intake, running wheel activity, body weight, and survival. Mechanistic studies used immunohistochemistry, gene expression analysis, and both mouse and human neuronal cell cultures to confirm TET3 degradation and neuropeptide upregulation.

What this study cannot tell us

The activity-based anorexia model captures some but not all aspects of human anorexia nervosa (a complex psychiatric condition with psychological, social, and genetic components). Bobcat339's selectivity for TET3 versus other TET family members (TET1, TET2) was not fully characterized, raising potential off-target concerns. Long-term safety of TET3 inhibition is unknown, as TET enzymes play broad roles in gene regulation. No human studies have been conducted.

How to read the evidence

Published in PNAS (top-tier journal), this is a rigorous preclinical study with mechanistic validation in both mouse and human cells. However, it remains animal-only data, and the activity-based anorexia model is a simplified representation of human anorexia nervosa.

When this study was published

Published in 2023, this study is very recent and represents a novel therapeutic approach to anorexia nervosa — a condition with essentially no approved pharmacological treatments.

The bigger picture

This study bridges epigenetics (TET3 is a DNA-modifying enzyme) and neuropeptide biology, showing that upstream epigenetic regulators control the expression of key appetite peptides. It also demonstrates a new therapeutic principle: rather than directly administering neuropeptides (which don't cross the blood-brain barrier easily), you can use small molecules to boost endogenous neuropeptide production from the inside. This approach could be applicable beyond anorexia to other conditions involving neuropeptide dysregulation.

Questions still open

Would Bobcat339 or similar TET3 inhibitors be safe and effective in human anorexia nervosa patients?
Could upregulating AgRP/NPY through TET3 inhibition cause excessive weight gain or metabolic complications?
Does TET3 inhibition affect other brain circuits beyond AgRP neurons, and what would be the broader neuropsychiatric implications?

Common questions

Why is it so hard to treat anorexia nervosa with drugs?

Anorexia involves a complex interplay of psychology, brain chemistry, and genetics. The brain's hunger signals (driven by peptides like AgRP and NPY) become dysregulated, but these peptides can't be simply given as drugs because they don't cross from the blood into the brain. This study found a way around that problem — a small molecule that boosts the brain's own production of hunger peptides.

What are AgRP and NPY and why are they important for appetite?

AgRP and NPY are two of the most powerful appetite-stimulating peptides in the brain, produced by specific neurons in the hypothalamus. When these neurons are active, they drive intense hunger and feeding behavior. In anorexia, these signals may be suppressed. This study shows that degrading the enzyme TET3 activates these neurons and increases AgRP/NPY production, restoring the drive to eat.

Read the original research

A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Proceedings of the National Academy of Sciences of the United States of America, 120(16), e2300015120

View on PubMed ↗Publisher’s paper ↗

Citation

Lv, Haining; Catarino, Jonatas; Li, Da; Liu, Beibei; Gao, Xiao-Bing; Horvath, Tamas L; Huang, Yingqun. (2023). A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.. Proceedings of the National Academy of Sciences of the United States of America, 120(16), e2300015120. https://doi.org/10.1073/pnas.2300015120