New Brain Pathway Targeted for Weight Loss Without GI Side Effects

A groundbreaking study has unveiled a novel approach to weight loss that could potentially revolutionize obesity treatment. Scientists have successfully targeted a pathway deep in the brain to promote weight reduction in obese rodents without the gastrointestinal side effects commonly associated with current treatments.

ODN: A Promising Alternative to GLP-1 Therapies

Researchers led by Caroline Geisler, Ph.D., a pharmacologist at the University of Kentucky, have focused on octadecaneuropeptide (ODN), a small protein produced by glial cells in the hindbrain. By injecting a modified version of ODN into obese mice daily for nine days, the team observed consistent weight loss without the typical nausea or vomiting behaviors seen with GLP-1 drugs like semaglutide and tirzepatide.

The study, published in Science Translational Medicine on July 23, 2025, demonstrates that ODN could "serve a population of people who cannot tolerate the GLP-1 therapies," according to Geisler. This is particularly significant given that GLP-1 therapies, despite their effectiveness, have a discontinuation rate of over 50%, largely due to side effects.

Mechanism and Future Prospects

ODN is produced by non-neuron cells called glia in the hindbrain, which monitor nutrient levels in the bloodstream. When imbalances are detected, these cells release signaling molecules like ODN to direct neurons to take action. The researchers used a smaller, modified version of ODN called trideca-neuropeptide (TDN), which can more easily cross the blood-brain barrier.

Geisler and her colleagues are now working to enhance ODN's longevity in the body, with the goal of initiating early human trials within two to three years. If successful, this approach could tap into the massive market currently dominated by GLP-1 drugs, which are projected to make up 9% of all prescription drug sales by 2030.

Potential Market Impact

The development of a non-nauseating obesity drug based on ODN could have significant implications for the pharmaceutical industry. Data analytics firm Evaluate Pharma projects that GLP-1 drugs will constitute a substantial portion of prescription drug sales by 2030, with Eli Lilly's Zepbound (tirzepatide) alone expected to earn $25.5 billion that year. A more tolerable alternative could potentially capture a significant share of this growing market.