New Ozempic: Scientists Hack The Brain And Create Obesity Drug Without Nausea And Vomiting

Scientists have discovered that a molecule produced by brain support cells, called ODN, can help reduce appetite and improve glucose control without causing side effects such as nausea and vomiting. A modified version, TDN, has shown promising results in animal trials and could become a safer alternative to current weight loss and diabetes medications, with human trials expected in 2026 or 2027.

Researchers are investigating safer and more effective ways to help people lose weight and manage diabetes without the unpleasant side effects of current medications. Most medications used today, such as Ozempic and Zepbound, act directly on the neurons in the brain responsible for the sensation of hunger.

While these medications help many people lose weight, they often cause side effects such as nausea and vomiting, which leads about 70% of patients to discontinue treatment within a year.

In search of alternatives, scientists from Syracuse University and SUNY Upstate Medical University decided to explore a largely understudied area: the brain's supporting cells, called glia and astrocytes. Unlike neurons, these cells don't transmit electrical signals, but they are essential for keeping the brain functioning properly.

The researchers discovered that these cells, located in a region of the brain called the hindbrain, naturally produce a substance called octadecanoeuropeptide (ODN). This molecule has an anorectic effect, meaning it reduces appetite.

When the scientists injected ODN directly into the brains of rats, they observed reduced food intake, weight loss, and improved glucose control, without causing nausea, vomiting, or other unwanted side effects.

A microscopic view of the hindbrain reveals "supporting cells" (highlighted in green, red, yellow, and purple) that produce molecules that suppress appetite. Researchers at Syracuse University are using these cells to develop nausea-free weight loss treatments. Source: Syracuse University.

It was also noted that ODN did not affect the animals' body temperature, heart rate, or physical activity. Furthermore, the researchers found that by blocking ODN's action in the brain, the appetite-suppressing effects of GLP-1 medications diminished, indicating that ODN is one of the agents responsible for this action in the body.

However, injecting substances directly into the brain is not a viable option for human treatment. To address this problem, the team created a modified version of the molecule, called tridecanoeuropeptide (TDN). This new form can be administered through regular injections, just like existing medications.

In tests with obese mice and musk shrews (a small mammal that, unlike most rodents, can vomit), TDN had similar positive effects: it improved insulin sensitivity, reduced appetite, and led to weight loss, all without causing nausea or vomiting.

The unique feature of this new method is that, instead of acting directly on neurons and triggering a long chain of reactions (which includes side effects on the digestive system), TDN acts "further down the chain," at a more direct point in the process that regulates appetite.

According to the researchers, it's like starting a race halfway through, sparing the body all the effort (and side effects) of the initial leg. This alternative approach could make treatments more tolerable for patients or even allow for the use of lower doses of current medications.

Professor Robert Doyle, who led the study.

"If we could target this downstream process directly, we potentially wouldn't have to use GLP-1 medications with their accompanying side effects," Doyle adds. "Or we could reduce the dose, improving tolerance to these medications."

To turn this discovery into a real treatment, the researchers founded a company called CoronationBio, which has already licensed the rights to ODN derivatives and is working with other organizations to develop TDN-based medications. If all goes well, the first human trials could begin between 2026 and 2027.

This line of research paves the way for a new generation of weight management and diabetes medications that work differently, are safer, and have fewer side effects, improving the quality of life of patients who rely on these therapies.

READ MORE:

Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis

CAROLINE E. GEISLER, KYLIE S. CHICHURA, OLEKSANDR ORATIVSKYI, 

JIAYIN HU, DREW L. BELSER, CAITLYN M. PELLETIER, TITO BORNER, 

CAITLIN BAUMER-HARRISON, BART C. DE JONGHE, RICHARD C. CRIST, BENJAMIN C. REINER, ROBERT P. DOYLE, AND MATTHEW R. HAYES 

SCIENCE TRANSLATIONAL MEDICINE, 23 Jul 2025, Vol 17, Issue 808

DOI: 10.1126/scitranslmed.adu6764

Abstract: 

Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.