Scientists at Stanford Medicine have identified a naturally occurring molecule that can suppress appetite and reduce body weight in a way that resembles semaglutide, the active ingredient in Ozempic. In animal studies, this molecule also proved to help avoid many of the problems associated with the drug, including nausea, constipation, and loss of substantial muscle mass.
The molecule, known as BRP, works through a different but related metabolic pathway and activates a different group of neurones in the brain. This difference may make it a more accurate tool for controlling appetite and body weight.
A more targeted approach to appetite control
“The receptors targeted by semaglutide are found in the brain but also in the intestine, pancreas, and other tissues,” said Katrin Svensson, PhD, assistant professor of pathology. “This is why Ozempic has a wide range of effects that include slowing the movement of food through the digestive tract and reducing blood sugar levels. In contrast, BRP acts specifically in the hypothalamus, which regulates appetite and metabolism.”
The hypothalamus is a small area within the brain that helps regulate appetite, body temperature, hormone activity, and energy use. Because BRP appears to act primarily in this area, it may affect appetite without causing much effect elsewhere in the body.
Svensson has co-founded a company that plans to begin clinical testing of the molecule in humans in the near future.
Svensson is the senior author of the research published March 5 in Nature. Senior Research Scientist Letitia Coasolo, PhD, is the study’s lead author.
Artificial intelligence reveals hidden peptides
The discovery relied largely on artificial intelligence, which allowed researchers to search through proteins belonging to a group called 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, carrying signals that influence metabolism, appetite, and other complex processes in the brain and throughout the body.
A single prohormone can be cut in many different ways, producing many possible peptides. Biologically important ones are difficult to identify because actual peptide hormones are relatively rare and may be buried among the large number of common fragments during normal protein processing and breakdown.
Traditional laboratory methods can isolate and identify peptides, but the process can generate enormous amounts of data. Researchers may need to sort through hundreds of thousands of molecules to find a few that have a meaningful effect.
Discovery of new metabolic signals
The team focused on an enzyme called prohormone convertase 1/3. This enzyme cleaves the prohormone 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 control appetite and blood sugar, and semaglutide works by mimicking its effects in the body.
The researchers reasoned that the same enzyme might produce other peptides that affect energy balance and appetite. To identify them, they turned to artificial intelligence.
The scientists created a computer algorithm called ‘Peptide Predictor’
The scientists created a computer algorithm called ‘Peptide Predictor’ to automate the extraction of proteins and peptides from tissues, rather than manually using methods such as mass spectrometry to identify large numbers of molecules.
The programme searched all 20,000 human protein-coding genes for the types of sites where prohormone convertases typically cleave proteins. The researchers then narrowed the search to genes that produce proteins secreted outside the cell, a common feature of hormones, and that contain at least four potential cleavage sites.
That process narrowed the field to 373 prohormones, giving the team a more manageable group to investigate.
“The algorithm was absolutely critical to our findings,” Svensson said.
Peptide Predictor predicted that prohormone convertase 1/3 could produce 2,683 different peptides from those 373 proteins. Coasolo and Svensson then focused on the sequences that were most likely to affect the brain.
They selected 100 peptides, including GLP-1, and tested whether they could stimulate neurone-like cells grown in the lab.
A small peptide with a big impact
As expected, GLP-1 strongly activated the neuronal cells, increasing their activity threefold above the level seen in untreated control cells.
A much smaller peptide produced an even more dramatic response. Composed of only 12 amino acids, it increased neuronal activity tenfold compared to the control.
The researchers named the peptide BRP after its parent prohormone, BPM/retinoic acid-inducible neural-specific 2, or BRINP2 (BRINP2-related peptide).
Amino acids are the basic building blocks of proteins and peptides. A molecule containing only 12 of them is extremely small compared to most full-sized proteins, yet BRP produced the strongest response in initial cell tests.
Up to 50% drop in food intake
The researchers next tested BRP in lean mice and minipigs (which more closely reflect human metabolism and eating patterns than rats).
Intramuscular injection given before feeding reduces food intake by 50% during the next hour in both species.
The team also gave BRP injections to obese mice daily for 14 days. Treated animals lost an average of 3 grams of weight, with almost all of the loss coming from body fat. During the same period, the weight of rats in the control group increased by about 3 grams.
The treated rats also showed improvements in glucose and insulin tolerance. These tests show how well the body controls blood sugar and how well it responds to insulin, the hormone that helps move glucose from the blood into cells.
No obvious signs of common side effects
Behavioural testing revealed no significant differences in activity, water consumption, anxiety-like behaviour or faecal production between treated and untreated animals.
The absence of changes in stool output was particularly notable because semaglutide can slow digestion and cause constipation. The researchers also did not see any nausea-related side effects or major muscle loss that can happen with some current weight loss treatments.
Further assessments of cerebral activity and physiological function indicated that BRP operates via metabolic and neuronal pathways distinct from those engaged by GLP-1 or semaglutide.
Those findings suggest that BRP may reduce appetite through a more focused biological pathway, although the results are limited to animals.
Questions before human testing
Researchers are now working to identify the cell-surface receptors that bind to BRP. Receptors are molecular structures that receive signals from hormones, drugs, and other chemical messengers. Determining which receptor BRP uses will help scientists understand how the peptide alters appetite and metabolism.
The team also wants to map the entire sequence of events that occur after BRP binds to its target.
Another challenge is duration. Small peptides often break down quickly in the body, which may reduce their effectiveness. Researchers are investigating ways to make BRP last longer so that, if it eventually works in people, it can be administered at a more practical time.
“The lack of effective drugs to treat obesity in humans has been a problem for decades,” Svensson said. “Nothing we have tested before has compared semaglutide’s ability to reduce appetite and body weight. We are very keen to learn whether 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 this work.
The study was funded by the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618 and GM113854), the SPARC 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 Fellowship Award, the Carlsberg Foundation, and the Harvard Medical School. Wu Tsai Human Performance Alliance.
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