Novel Brain-Targeting Approach Shows Promise for Obesity Treatment Without GI Side Effects

Researchers have discovered a potential new avenue for treating obesity that could avoid the gastrointestinal side effects commonly associated with current weight-loss medications. The breakthrough, involving a modified version of a naturally occurring brain peptide, has shown promising results in animal studies and could lead to the development of more tolerable obesity treatments for humans.

Targeting Deep Brain Pathways for Weight Loss

Scientists from the University of Kentucky, Syracuse University, and the University of Pennsylvania have successfully demonstrated that targeting a specific pathway deep in the brain can promote weight loss in small mammals without causing gastrointestinal distress. The research, published in Science Translational Medicine on July 23, 2025, focused on a modified version of octadecaneuropeptide (ODN), a small protein produced by glial cells in the hindbrain.

Dr. Caroline Geisler, lead author of the study and pharmacologist at the University of Kentucky, explained the significance of their findings: "Should ODN's effects translate to humans, the protein could serve a population of people who cannot tolerate the GLP-1 therapies. That is the number one issue with the GLP-1 therapies that are obviously leading the market right now, they have an over 50% discontinuation rate in large part due to the side effects."

Promising Results in Animal Studies

The research team conducted experiments on obese mice, rats, and shrews, administering daily injections of a modified ODN called trideca-neuropeptide (TDN) for nine days. The results were consistently positive, with the animals showing significant weight loss without exhibiting the typical nausea or vomiting behaviors associated with GLP-1 drugs like semaglutide and tirzepatide.

TDN, a smaller version of ODN, was designed to more effectively cross the blood-brain barrier when administered through the bloodstream. This approach could potentially overcome the limitations of direct brain injections, which are not feasible in human patients.

Potential Market Impact and Future Developments

The development of a non-nauseating obesity drug could have substantial market implications. Data analytics firm Evaluate Pharma projects that GLP-1 drugs will constitute 9% of all prescription drug sales by 2030, with Eli Lilly's Zepbound (tirzepatide) expected to generate $25.5 billion in revenue that year.

Dr. Geisler and her colleagues are currently working to optimize TDN for longer-lasting effects in the body. They aim to initiate early human trials within the next two to three years, potentially paving the way for a new class of obesity treatments that could address the high discontinuation rates of current therapies due to side effects.