Scientists at Stanford Medicine have identified a natural molecule that appears to mimic some of the weight-loss effects of semaglutide, commonly known as Ozempic. In animal studies, this molecule reduced appetite and weight while avoiding some common side effects such as nausea, constipation, and muscle loss.
This molecule, called BRP, acts through different but related biological pathways to activate different groups of neurons in the brain. This suggests it may offer a more precise way to control appetite and metabolism.
“The receptors that semaglutide targets are located not only in the brain, but also in the intestines, pancreas, and other tissues,” said Dr. Katrin Svensson, assistant professor of pathology. “That’s why Ozempic has far-reaching effects, including slowing the movement of food through the gastrointestinal tract and lowering blood sugar levels. In contrast, BRP appears to act specifically in the hypothalamus, which controls appetite and metabolism.”
Mr. Svensson naturealso co-founded a company that plans to begin human clinical trials in the near future. The study’s lead author is senior researcher Dr. Leticia Coasolo.
How did artificial intelligence come to the discovery?
This discovery relied heavily on artificial intelligence to classify a large group of molecules known as prohormones. These molecules are initially inactive, but can be cut into smaller pieces called peptides, some of which act as hormones that affect processes such as metabolism in the brain and body.
Because each prohormone can be split in many different ways, it is very difficult to identify useful peptide hormones using traditional laboratory methods. Researchers often have trouble distinguishing these rare signaling molecules from the many inactive fragments produced during normal protein breakdown.
To narrow down their search, the research team focused on an enzyme called prohormone convertase 1/3. This enzyme cuts proteins at specific locations and has been linked to obesity. One well-known product of this process is glucagon-like peptide 1 (GLP-1), which helps regulate appetite and blood sugar levels. 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 a peptide predictor. The algorithm scanned all 20,000 human protein-coding genes to determine where prohormones are cleaved into peptides.
The researchers then zeroed in on proteins that are secreted outside the cell, are a key feature of hormones, and contain multiple potential break points. This reduced the list to 373 prohormones suitable for further testing.
“The algorithm was absolutely key to our discovery,” Svensson said.
From these proteins, the system predicted 2,683 possible peptides. The researchers selected 100 of them, including GLP-1, and tested how they affected brain cells grown in the lab.
A small peptide with powerful effects
As expected, GLP-1 significantly increased neuronal activity. However, one much smaller peptide, consisting of just 12 amino acids, produced an even stronger response, increasing activity 10-fold compared to control cells.
This peptide was named BRP after its parent molecule, BPM/retinoic acid-inducible neuron-specific 2, or BRINP2 (BRINP2-related peptide).
Animal experiments show decreased appetite and fat loss
When tested in lean mice and minipigs (which more closely reflect human metabolism and dietary patterns than mice), BRP significantly reduced food intake. A single injection before breastfeeding reduced consumption by up to 50% within an hour.
In obese mice, daily injections over 14 days resulted in an average weight loss of 3 grams, primarily due to fat. In contrast, untreated mice gained about 3 grams over the same period. Treated animals also showed improved glucose tolerance and insulin resistance.
Importantly, no changes were observed in the animals’ movements, water intake, anxiety-like behavior, or digestion. Additional analyzes confirmed that BRP acts through different brain and metabolic pathways than GLP-1 and semaglutide.
A more targeted approach to weight loss
Researchers are currently working to identify the specific receptors that interact with BRP to better understand how BRP functions in the body. They are also exploring ways to expand its effectiveness to make it more convenient to use if it proves effective in humans.
“The lack of effective drugs to treat obesity in humans has been a problem for decades,” Svensson said. “Nothing we have tested so far compares to semaglutide’s ability to reduce appetite and weight. We are very keen to know whether it is safe and effective in humans.”
Collaboration and funding
The study involved scientists from the University of California, Berkeley. University of Minnesota. and the University of British Columbia. Funding was provided by the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618, GM113854), as well as several programs at Stanford University, 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 diseases, and Svensson is a co-founder of Merrifield Therapeutics.
