Scientists at Stanford Medicine have identified a naturally occurring 12-amino-acid molecule that could eventually lead to a new type of weight-loss treatment. Called BRP, the peptide reduced food intake and promoted fat loss in mice and minipigs, while appearing to avoid some digestive and behavioral effects associated with semaglutide, the active ingredient in Ozempic. However, BRP has only been tested in laboratory cells and animals, so its safety and effectiveness in people remain unknown.
A different approach to weight loss
BRP appears to work differently from existing treatments. Rather than acting across several organs, it seems to target specific areas of the brain involved in hunger and metabolism. This selectivity could eventually allow it to suppress appetite while reducing problems such as nausea, constipation, and significant muscle loss, although human studies are needed to determine whether that is possible.
“The receptors that semaglutide targets are located not only in the brain, but also in the intestine, 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, energy use, body temperature, and other functions needed to maintain the body’s internal balance. Its role in appetite makes it an important target for obesity research.
Semaglutide mimics glucagon-like peptide 1 (GLP-1), a hormone that helps regulate blood sugar and sends signals related to hunger and satiety. GLP-1 receptors are distributed throughout the body, which helps explain why drugs that activate them can affect more than appetite.
BRP appears to influence some of the same broad metabolic functions as semaglutide, but it activates a different population of brain cells. Researchers believe this difference could enable more precise control of hunger while limiting effects on other tissues.
Svensson, who was the study’s senior author, co-founded a company to advance BRP toward human clinical trials. The study was led by Senior Researcher Dr. Leticia Coasolo.
How artificial intelligence helped uncover BRP
Finding BRP required researchers to address a longstanding challenge in the search for hormones. The human body produces vast numbers of small protein fragments, but only a small proportion have important biological functions. Identifying which fragments influence appetite and metabolism can be difficult.
Many hormones begin as larger, inactive proteins called prohormones. Enzymes cut these proteins into smaller pieces known as peptides. Some of those peptides act as chemical messengers involved in energy metabolism, appetite, and organ function.
A single prohormone can be cut at several locations, producing numerous peptides with different effects. Researchers must determine which fragments serve useful biological roles and which are simply byproducts of normal protein processing. Important peptide hormones are relatively rare compared with the much larger collection of ordinary protein fragments.
Traditional methods often extract proteins from biological tissues and analyze them with techniques such as mass spectrometry. These methods identify molecules by measuring properties related to their mass, but the sheer number of possible peptides makes the search for new hormones difficult.
The Stanford team took a different approach. It focused on prohormone convertase 1/3, an enzyme that cuts prohormones at specific amino acid sequences and has previously been linked to obesity in humans. Amino acids are the molecular building blocks of proteins, and their arrangement helps determine where enzymes can cut them.
GLP-1 is one hormone produced through this type of processing. The researchers reasoned that other peptides generated in a similar way might also regulate appetite and energy use.
Searching 20,000 human genes
To accelerate the search, the scientists created a computer algorithm called Peptide Predictor. Rather than physically isolating and testing hundreds of thousands of peptides, the program analyzed roughly 20,000 genes that code for human proteins. It looked for sequences likely to be cut by prohormone convertase 1/3.
The researchers then narrowed the results to genes associated with proteins released outside cells, a common characteristic of hormones. Each candidate protein also had to contain at least four potential cleavage sites.
These filters reduced the possibilities to 373 prohormones, making experimental testing more practical.
“The algorithm was absolutely key to our discovery,” Svensson said.
Peptide Predictor estimated that the enzyme could generate 2,683 different peptides from those 373 proteins. Svensson and Coasolo selected candidates they considered especially likely to affect brain activity.
The team ultimately tested 100 peptides, including GLP-1, using nerve cells grown in the laboratory. The researchers were looking for substances that could stimulate neuronal activity, an early indication that a peptide might affect important brain processes.
A 12-amino-acid peptide shows strong activity
GLP-1 increased neural activity threefold compared with untreated control cells. One previously unrecognized peptide produced an even stronger response: despite consisting of only 12 amino acids, it increased neuronal activity tenfold compared with controls.
The researchers named the molecule BRP after its larger source protein, BPM/retinoic acid-inducible neuron-specific 2, or BRINP2. BRP stands for BRINP2-related peptide.
The strong response made BRP a promising candidate for further study. The next question was whether stimulating brain cells in the laboratory would lead to meaningful changes in appetite and body weight in living animals.
Animal studies reduced food intake and preserved muscle
The researchers tested BRP in lean mice and minipigs, which more closely reflect human metabolism and dietary patterns than mice. They administered the peptide by intramuscular injection before feeding the animals.
During the following hour, treated animals ate up to 50% less food than expected, suggesting that BRP can have a strong effect on hunger.
The team then examined whether repeated treatment could produce lasting weight changes. Obese mice received daily BRP injections for 14 days. By the end of the experiment, treated mice had lost an average of 3 grams, while untreated control mice had gained about 3 grams.
Nearly all of the weight lost by the BRP-treated mice came from body fat rather than muscle. Preserving muscle is an important goal in obesity treatment because muscle supports strength, mobility, and metabolic health.
The treated animals also showed improved glucose tolerance and insulin resistance. These measures indicate how effectively the body processes sugar and responds to insulin, the hormone that helps move glucose from the bloodstream into cells.
Together, the findings suggest that BRP can affect both appetite and metabolic health. It remains unclear, however, whether people would experience comparable effects.
Could BRP avoid some side effects of semaglutide?
One notable aspect of the findings is the possibility that BRP could provide weight-loss benefits without some unwanted effects associated with semaglutide and similar drugs.
To investigate potential side effects, the researchers monitored the behavior and physical responses of treated mice and pigs. They found no significant differences from control animals in movement, water consumption, anxiety-related behaviors, or fecal output.
The unchanged fecal output was notable because constipation is a known side effect of drugs such as Ozempic. The experiments also indicated that BRP promoted fat loss without the substantial muscle loss associated with some weight-loss treatments.
Nausea is another common concern with existing GLP-1 treatments, but animal studies cannot establish whether BRP would prevent that symptom in humans. Human trials will be needed to determine the molecule’s actual side-effect profile.
Additional studies of brain activity and other physiological responses supported the idea that BRP works differently from semaglutide. Instead of simply copying GLP-1’s effects, the peptide activated different neural and metabolic pathways.
This distinction may explain why BRP produced strong appetite suppression without some of the behavioral and digestive changes observed with other treatments.
What researchers need to learn next
BRP is still in the early stages of development. Researchers must determine how the molecule communicates with cells and how long its effects last.
One priority is identifying the cell-surface receptors that recognize BRP. These specialized proteins respond to specific chemical signals, allowing cells to detect messages and trigger biological responses. Finding the receptors activated by BRP could help explain its effects on hunger and metabolism.
The team also plans to investigate ways to extend the molecule’s activity in the body. Peptides break down relatively quickly and may require frequent injections. A longer-lasting version of BRP could make treatment more convenient if the molecule ultimately proves effective in people.
The central question is whether BRP’s apparent benefits in animals will translate into meaningful benefits for patients. Before it could become an obesity treatment, clinical trials would need to assess its safety, effectiveness, appropriate dosage, and potential side effects.
“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.”
Collaborators, funding, and disclosures
The study also involved scientists at the University of California, Berkeley, the University of Minnesota, and the University of British Columbia.
Funding came from the National Institutes of Health through grants R01DK125260, P30DK116074, K99AR081618, and 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 Coasolo are named inventors on a patent covering the use of BRP peptides to treat metabolic disorders. Svensson is also a co-founder of Merrifield Therapeutics.
Source: www.sciencedaily.com
