Stanford Medicine researchers have identified a natural molecule that can suppress appetite and reduce body weight in a similar way to semaglutide, the active ingredient in Ozempic. In animal studies, the molecule also appeared to prevent several problems associated with the drug, such as nausea, constipation, and substantial loss of muscle mass.
The molecule, known as BRP, works through a different but related metabolic pathway and activates a separate group of neurons in the brain. That distinction could make it a more precise tool for monitoring appetite and body weight.
A more targeted approach to appetite control
“The receptors that semaglutide targets are found in the brain but also in the intestine, pancreas and other tissues,” said assistant professor of pathology Katrin Svensson, PhD. “That’s why Ozempic has widespread effects that include slowing the movement of food through the digestive tract and lowering blood sugar levels. In contrast, BRP appears to act specifically on the hypothalamus, which controls appetite and metabolism.”
The hypothalamus is a small region deep within the brain that helps regulate hunger, body temperature, hormonal activity, and energy use. Because BRP appears to act primarily in this area, it may influence appetite without producing as many effects elsewhere in the body.
Svensson has co-founded a company that plans to begin clinical trials of the molecule in humans in the near future.
Svensson is the lead author of the research, which was published March 5 in Nature. Senior research scientist Laetitia Coassolo, PhD, is the lead author of the study.
Artificial intelligence reveals hidden peptides
The discovery relied heavily on artificial intelligence, which allowed researchers to search for proteins belonging to a group known as prohormones.
Prohormones are inactive precursor molecules. They do not perform their final biological function until enzymes cut them into smaller fragments called peptides. Some of these peptides then act as hormones, transmitting signals that influence metabolism, appetite, and other complex processes in the brain and throughout the body.
A single prohormone can be cleaved in several different ways, producing many possible peptides. Finding biologically important ones is difficult because genuine peptide hormones are relatively rare and can get buried among a large number of ordinary fragments created during the normal processing and breakdown of proteins.
Traditional laboratory methods can isolate and identify peptides, but the process can produce enormous amounts of data. Researchers may need to sort through hundreds of thousands of molecules to find the few that have significant effects.
Searching for new metabolic signals
The team focused on an enzyme called prohormone convertase 1/3. This enzyme cleaves prohormones at specific amino acid sequences and has previously been linked to obesity in humans.
One of the peptides produced through this process is glucagon-like peptide 1 or GLP-1. GLP-1 helps regulate hunger and blood sugar, and semaglutide works by copying its effects in the body.
The researchers reasoned that the same enzyme could produce other peptides that influence energy balance and appetite. To find them, they turned to artificial intelligence.
Peptide predictor
Instead of manually extracting proteins and peptides from tissues and then using methods such as mass spectrometry to identify large numbers of molecules, the researchers created a computer algorithm called Peptide Predictor.
The program searched the 20,000 human protein-coding genes for the types of sites where prohormone convertases typically cut proteins. The researchers then narrowed the search to genes that produce proteins secreted outside the cell, a common feature of hormones, and that contained at least four possible cleavage sites.
That process narrowed the field to 373 prohormones, giving the team a much more manageable pool to investigate.
“The algorithm was absolutely key to our findings,” Svensson said.
Peptide Predictor estimated that prohormone convertase 1/3 could produce 2,683 distinct peptides from those 373 proteins. Coassolo and Svensson then focused on the sequences that seemed most likely to affect the brain.
They selected 100 peptides, including GLP-1, and tested whether they could stimulate neuron-like cells grown in the lab.
A small peptide with a huge effect
As expected, GLP-1 strongly activated neuronal cells, increasing their activity to three times the level seen in untreated control cells.
A much smaller peptide produced an even more dramatic response. Made from just 12 amino acids, it increased neuronal activity tenfold compared to controls.
The researchers named the peptide BRP after its parent prohormone, BPM/neuronally inducible specific retinoic acid 2, or BRINP2 (BRINP2-related peptide).
Amino acids are the building blocks of proteins and peptides. A molecule containing only 12 of them is extremely small compared to most full-size proteins, but BRP produced the strongest response in initial cellular tests.
Food intake fell by up to 50%
Next, the researchers tested BRP in lean mice and minipigs (which more closely reflect human metabolism and eating patterns than mice).
An intramuscular injection given before feeding reduced food intake over the next hour by up to 50% in both species.
The team also gave daily injections of BRP to obese mice for 14 days. On average, treated animals lost 3 grams, and almost all of the reduction came from body fat. Mice in the control group gained about 3 grams during the same period.
The treated mice also showed better glucose and insulin tolerance. These measurements reflect how well the body regulates blood sugar and responds to insulin, the hormone that helps transport glucose from the bloodstream to cells.
No clear signs of common side effects
Behavioral testing found no significant differences between treated and untreated animals in movement, water consumption, anxiety-like behavior, or fecal production.
The lack of change in fecal output was especially notable because semaglutide can slow digestion and cause constipation. The researchers also did not look at responses related to nausea or significant muscle loss associated with some existing weight loss treatments.
Additional measurements of brain activity and body function showed that BRP acts through metabolic and neuronal pathways that differ from those activated by GLP-1 or semaglutide.
Those findings suggest that BRP may reduce appetite through a more focused biological route, although the results remain limited to animals.
Questions before human testing
Researchers are now working to identify cell surface receptors that bind BRP. Receptors are molecular structures that receive signals from hormones, drugs, and other chemical messengers. Determining which receptor BRP uses will help scientists understand exactly how the peptide changes appetite and metabolism.
The team also wants to map the full sequence of events that occur after BRP binds to its target.
Another challenge is duration. Small peptides tend to be broken down quickly in the body, which can shorten their effects. Researchers are investigating ways to make BRP last longer so that if it eventually works in people, it can be administered on a more practical schedule.
“The lack of effective drugs to treat obesity in humans has been a problem for decades,” Svensson said. “Nothing we have tried before has compared semaglutide’s ability to decrease appetite and body weight. We are very eager to know if it is safe and effective in humans.”
Researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia contributed to the work.
The study was funded by the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618, and GM113854), the SPARK Translational Research Program at Stanford, Stanford Bio-X, the Stanford Maternal and Child Health Research Institute, the American Heart Association, the Stanford Medicine Dean’s Scholarship Award, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance.
Svensson and Coassolo are patent inventors on BRP peptides for metabolic disorders. Svensson is co-founder of Merrifield Therapeutics.