Researchers at Stanford Medicine have identified a naturally occurring molecule that may suppress appetite and cause weight loss in a manner similar to semaglutide, the active ingredient in Ozempic. In animal studies, the molecule was also found to avoid some of the problems associated with the drug, including nausea, constipation, and significant muscle loss.
This molecule, known as BRP, acts through different but related metabolic pathways to activate different groups of neurons in the brain. This distinction could make it a more accurate tool for controlling appetite and weight.
A more targeted approach to controlling appetite
“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.”
The hypothalamus is a small region deep in the brain that helps regulate hunger, body temperature, hormonal activity, and energy use. Because BRP appears to act primarily in this area, it may affect appetite without having as much of an effect in other parts of the body.
Svensson co-founded a company that plans to begin human clinical trials of the molecule in the near future.
Svensson is the senior author of the study, which was published March 5 in the journal Nature. Senior Research Scientist Dr. Leticia Coresolo is the study’s lead author.
Artificial intelligence reveals hidden peptides
The discovery relied heavily on artificial intelligence, which allows researchers to search for proteins that belong to a group known as prohormones.
Prohormones are inactive precursor molecules. They do not perform their final biological function until they are cut into smaller pieces called peptides by enzymes. Some of these peptides act as hormones, transmitting signals that affect metabolism, appetite, the brain, and other complex processes throughout the body.
A single prohormone can be cleaved in several different ways to generate many peptides. True peptide hormones are relatively rare and can be buried among the many normal fragments produced during normal protein processing and degradation, making it difficult to find biologically significant ones.
Traditional laboratory methods can also isolate and identify peptides, but the process can generate vast amounts of data. Researchers may need to sort through hundreds of thousands of molecules to find the few that have meaningful effects.
Search for new metabolic signals
The research 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 (GLP-1). GLP-1 helps regulate hunger and blood sugar levels, and semaglutide works by mimicking its effects in the body.
The researchers reasoned that the same enzyme may produce other peptides that affect energy balance and appetite. To find them, they turned to artificial intelligence.
peptide predictor
Rather than manually extracting proteins and peptides from tissue and using methods such as mass spectrometry to identify vast numbers of molecules, the researchers created a computer algorithm called a peptide predictor.
The program searched all 20,000 human protein-coding genes for the types of sites where prohormone converting enzymes typically cut proteins. The researchers then narrowed their search to genes that produce proteins that are secreted outside the cell (a common feature of hormones), which contained at least four possible cleavage sites.
This process reduced the field to 373 prohormones and gave the team a much more manageable group to study.
“The algorithm was absolutely key to our discovery,” Svensson said.
Peptide Predictor estimated that prohormone convertase 1/3 could generate 2,683 different peptides from these 373 proteins. Coresolo and Svensson then zeroed in on the sequences they thought were 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 neurons, increasing their activity three-fold over the levels seen in untreated control cells.
One much smaller peptide caused an even more dramatic response. Made from just 12 amino acids, it increased neuronal activity 10 times compared to controls.
The researchers named this peptide BRP after its parent prohormone, BPM/retinoic acid-induced neurospecific 2, or BRINP2 (BRINP2-related peptide).
Amino acids are the basic building blocks of proteins and peptides. Although the molecule, which contains only 12 of them, is very small compared to most full-sized proteins, BRP showed the strongest response in the initial cell tests.
Food intake reduced by up to 50%
The researchers then tested BRP in lean mice and minipigs (which more closely reflect human metabolism and eating patterns than mice).
Intramuscular injections given before feeding reduced food intake by as much as 50% in the subsequent hour in both species.
The research team also gave obese mice daily BRP injections for 14 days. On average, treated animals lost 3 grams, and almost all of that loss was from body fat. Mice in the control group gained about 3 grams over the same period.
Treated mice also showed improved glucose tolerance and insulin resistance. These measurements reflect how effectively the body regulates blood sugar and responds to insulin, a hormone that helps move glucose from the bloodstream to cells.
No obvious signs of common side effects
Behavioral testing showed no significant differences in movement, water intake, anxiety-like behavior, or fecal secretion between treated and untreated animals.
The lack of change in fecal production is particularly noteworthy, as semaglutide can slow digestion and cause constipation. The researchers also did not observe nausea-related reactions or large muscle loss associated with some existing weight loss treatments.
Additional measurements of brain activity and physical function showed that BRP acts through different metabolic and neural pathways than those activated by GLP-1 and semaglutide.
These findings suggest that BRP may reduce appetite through more focused biological pathways, but the results are still limited to animals.
Questions before human testing
Researchers are currently working to identify the cell surface receptors that bind BRP. Receptors are molecular structures that receive signals from hormones, drugs, and other chemical messengers. Identifying which receptors BRP uses will help scientists understand exactly how the peptide changes appetite and metabolism.
The team also wants to map the complete sequence of events that occur after BRP binds to a target.
Another challenge is duration. Small peptides are often broken down quickly in the body, which can shorten their effectiveness. Researchers are studying ways to make BRP last longer so that it can be administered on a more realistic schedule if it eventually becomes 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.”
Researchers at the University of California, Berkeley. University of Minnesota. The University of British Columbia contributed to this research.
This research was supported by the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618, GM113854), Stanford University’s SPARK Translational Research Program, Stanford Bio-X, the Stanford Maternal and Child Health Institute, the American Heart Association, the Stanford Medical Director’s Fellowship Award, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance.
Svensson and Coassolo are the inventors of a patent on BRP peptides for metabolic disorders. Svensson is a co-founder of Merrifield Therapeutics.
