Stanford scientists discover “natural Ozempic” without side effects

A newly discovered peptide could rival Ozempic — but with fewer side effects and a more targeted approach to weight loss.

Stanford Medicine

Scientists at Stanford Medicine have identified a naturally occurring molecule that appears to mimic some of the weight loss effects of semaglutide, the drug widely known as Ozempic. In animal studies, the molecule reduced appetite and body weight while avoiding several common side effects such as nausea, constipation, and muscle loss.

The molecule, called BRP, works through a different but related biological pathway and activates distinct groups of neurons in the brain. This suggests it may offer a more precise way to control appetite and metabolism.

"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," said assistant professor of pathology Katrin Svensson, PhD. "That's why Ozempic has widespread effects including slowing the movement of food through the digestive tract and lowering blood sugar levels. In contrast, BRP appears to act specifically in the hypothalamus, which controls appetite and metabolism."

Svensson, the senior author of the study published in Nature, has also co-founded a company that plans to begin human clinical trials in the near future. The study's lead author is senior research scientist Laetitia Coassolo, PhD.

How Artificial Intelligence Led to the Discovery

The discovery relied heavily on artificial intelligence to sort through a large group of molecules known as prohormones. These molecules are initially inactive but can be cut into smaller fragments called peptides, some of which function as hormones that influence processes like metabolism in the brain and body.

Because each prohormone can be split in many different ways, identifying useful peptide hormones using traditional lab methods is extremely challenging. Researchers often struggle to distinguish these rare signaling molecules from the many inactive fragments created during normal protein breakdown.

To narrow the search, the team focused on an enzyme called prohormone convertase 1/3, which cuts proteins at specific locations and has been linked to obesity. One well-known product of this process is glucagon-like peptide 1, or GLP-1, which helps regulate appetite and blood sugar. Semaglutide works by mimicking GLP-1.

"Peptide Predictor" Identifies Thousands of Candidates

Instead of relying on traditional protein analysis methods, the researchers developed a computer tool called Peptide Predictor. This algorithm scanned all 20,000 human protein-coding genes to identify where prohormones could be cut into peptides.

The team then narrowed their focus to proteins that are secreted outside cells, a key feature of hormones, and that contain multiple potential cleavage points. This reduced the list to 373 prohormones suitable for further testing.

"The algorithm was absolutely key to our findings," Svensson said.

From these proteins, the system predicted 2,683 possible peptides. Researchers selected 100 of them, including GLP-1, and tested how they affected lab-grown brain cells.

A Tiny Peptide With Powerful Effects

As expected, GLP-1 significantly increased activity in the neurons. However, one much smaller peptide, made up of only 12 amino acids, produced an even stronger response, boosting activity tenfold compared to control cells.

This peptide was named BRP, after its parent molecule BPM/retinoic acid inducible neural specific 2, or BRINP2 (BRINP2-related-peptide).

Animal Studies Show Reduced Appetite and Fat Loss

When tested in lean mice and minipigs (which more closely mirror human metabolism and eating patterns than mice do), BRP significantly reduced food intake. A single injection before feeding lowered consumption by up to 50% within an hour.

In obese mice, daily injections over 14 days led to an average weight loss of 3 grams, primarily from fat. In contrast, untreated mice gained about 3 grams during the same period. The treated animals also showed improvements in glucose and insulin tolerance.

Importantly, the animals did not show changes in movement, water intake, anxiety-like behavior, or digestion. Additional analyses confirmed that BRP works through different brain and metabolic pathways than GLP-1 or semaglutide.

A More Targeted Approach to Weight Loss

The researchers are now working to identify the specific receptors that interact with BRP and to better understand how it functions in the body. They are also exploring ways to extend its effects so it could be used more conveniently if it proves effective in people.

"The lack of effective drugs to treat obesity in humans has been a problem for decades," Svensson said. "Nothing we've tested before has compared to semaglutide's ability to decrease appetite and body weight. We are very eager to learn if it is safe and effective in humans."

Collaboration and Funding

The research involved scientists from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Funding came from the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618 and GM113854), along with several Stanford programs, the American Heart Association, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance.

Svensson and Coassolo are listed as inventors on patents related to BRP peptides for metabolic disorders, and Svensson is a co-founder of Merrifield Therapeutics.

Journal Reference:

1. Laetitia Coassolo, Niels B. Danneskiold-Samsøe, Quennie Nguyen, Amanda Wiggenhorn, Meng Zhao, David Cheng-Hao Wang, David Toomer, Jameel Lone, Yichao Wei, Aayan Patel, Irene Liparulo, Deniz Kavi, Lianna W. Wat, Saranya Chidambaranathan Reghupaty, Julie Jae Kim, Tina Asemi, Ewa Bielczyk-Maczynska, Veronica L. Li, Maria Dolores Moya-Garzon, Nicole A. J. Krentz, Andreas Stahl, Danny Hung-Chieh Chou, Liqun Luo, Katrin J. Svensson. Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide. Nature, 2025; 641 (8061): 192 DOI: 10.1038/s41586-025-08683-y