GLP-1 (glucagon-like peptide-1) drugs have ushered in a new era of pharmaceutical treatment for diabetes and obesity. But real-world studies show that many patients don’t stay on them for long.
Nearly a third of patients stop within four weeks, and estimates suggest around 50 to 60 percent of patients discontinue use at one year. One of the leading factors is the side effects that almost all patients experience at least initially, which most commonly include nausea, vomiting, constipation, and diarrhea.
Looking for relief
Scientists are now searching for the next generation of weight loss drugs that won’t cause the same unpleasant side effects. A new study published in Science Translational Medicine last month showed that a molecule produced in the hindbrain by glial cells, octadecaneuropeptide (ODN), could suppress appetite, induce weight loss, and improve the regulation of glucose in the body in obese rodent models — without the gastrointestinal side effects.
Specifically, the researchers did not observe pica behavior, a proxy for nausea in rats, or vomiting in the musk shrew, suggesting that it could potentially translate into a novel alternative to GLP-1 drugs with fewer adverse reactions in humans.
The team initially injected ODN directly into the rodents’ brains, but in order to have a more feasible injectable option for humans, they developed a synthetic version called tridecaneuropeptide (TDN) that they administered peripherally to the animals. The exact neurobiological underpinnings of TDN still need further study, as will the confirmation that TDN is actually penetrating into the brain.
However, the authors proposed that unlike GLP-1 drugs that bind to the GLP-1 receptor on neurons, ODN and TDN instead act on downstream glial cells that support neurons, working to modulate the activation of GLP-1 receptors via pathways in the hypothalamic and hindbrain indirectly.
“If we could hit that downstream process directly, then potentially we wouldn’t have to use GLP-1 drugs with their side effects. Or we could reduce their dose, improving the toleration of these drugs,” said Robert Doyle, a medicinal chemist at Syracuse University who co-led the study.
Promise and pitfalls
Other scientists in the field are encouraged by the potential to target a new mechanism. “Identification of a pathway and molecule enabling robust suppression of appetite and weight loss while avoiding aversive responses would be a real breakthrough for development of weight loss medicines,” Daniel Drucker, an endocrinologist at the Lunenfeld-Tanenbaum Research Institute and a recent winner of the 2025 Breakthrough Prize in Life Sciences, told DDN.
Yet, translating the findings into humans remains a long way off. “While the findings are intriguing and introduce a novel player in the field, substantial questions remain before this pathway can be considered a strong candidate for obesity drug development,” Marzieh Salehi, an endocrinologist at the University of Texas Health at San Antonio, told DDN. “Key uncertainties include the human translational relevance of the gliopeptide system, the stability and bioavailability of TDN in humans, potential off-target CNS effects, and the consequences of chronically manipulating glial function.”
To continue investigating TDN and other ODN derivatives, the press release stated that a new biotech company called CoronationBio has licensed the intellectual property from Syracuse University and the University of Pennsylvania and plans to begin human trials in 2026 or 2027.
