Stanford Medicine scientists have identified a natural molecule that could lead to a new generation of weight-loss drugs. Early animal experiments suggest it may suppress appetite and promote fat loss, much like semaglutide, the active ingredient in Ozempic, while potentially avoiding some of the drug’s bothersome side effects.
The molecule, known as BRP, works differently from existing treatments. Rather than affecting multiple organs in the body, it appears to act more selectively on a part of the brain responsible for controlling hunger and metabolism. This more targeted approach could potentially help people lose weight without experiencing problems such as nausea, constipation, or significant muscle loss.
Researchers discovered BRP using artificial intelligence, which allowed them to search for thousands of possible biological compounds. The results were promising enough for scientists to prepare for the next major step: determining whether the molecule is safe and effective in humans.
“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 broad effects, including slowing the movement of food through the digestive tract and lowering blood sugar levels. In contrast, BRP appears to act specifically in the hypothalamus, which controls appetite and metabolism.”
A different approach to weight loss
The hypothalamus is a small but essential region located deep within the brain. Among its many responsibilities, it helps regulate hunger, energy consumption, body temperature and other functions necessary to maintain the body’s internal balance. Because it plays a central role in appetite, it is an important target for researchers developing treatments for obesity.
Semaglutide works by mimicking a hormone called glucagon-like peptide 1, or GLP-1. This hormone helps regulate blood sugar and the signals that influence hunger and feelings of fullness. However, GLP-1 receptors are distributed in several parts of the body, which explains why drugs that activate them can produce effects beyond appetite suppression.
BRP appears to be taking a different path. Although it influences some of the same metabolic functions as semaglutide, it activates different populations of brain cells. Scientists believe this distinction could allow for more precise control of hunger while reducing adverse effects elsewhere in the body.
Svensson, who was lead author of the study, published in Naturealso co-founded a company aimed at advancing BRP into human clinical trials. The research was led by principal investigator Laetitia Coassolo, PhD.
How artificial intelligence discovered a hidden molecule
Finding BRP required solving a problem that has long complicated the search for new hormones. The human body produces an enormous number of small protein fragments, but only a fraction of them have important biological functions. Identifying those that influence appetite or metabolism can be extremely difficult.
Many hormones start as larger, inactive proteins called prohormones. Specialized enzymes cut these proteins into smaller pieces called peptides. Some of these peptides become chemical messengers that help coordinate processes such as energy metabolism, appetite and organ function.
A single prohormone can be cut in several different places, potentially producing many peptides with distinct effects. The challenge is to determine which fragments are biologically useful and which are simply leftovers from normal protein processing. Important peptide hormones (which are relatively rare) can be difficult to distinguish from the much larger collection of ordinary protein fragments.
Traditional approaches often involve extracting proteins from biological tissues and analyzing them using techniques such as mass spectrometry. This method identifies molecules by measuring characteristics related to their mass, but the large number of possible peptides makes the search for new hormones a demanding process.
The Stanford team decided to approach the problem differently. They focused on an enzyme called prohormone convertase 1/3, which cuts prohormones at particular amino acid sequences and has previously been linked to human obesity. Amino acids are the molecular building blocks of proteins, and their arrangement determines where enzymes can cut them.
One of the hormones produced during this process is GLP-1, the same hormone whose effects mimic semaglutide. The researchers reasoned that other peptides generated by similar treatment might also help regulate appetite and energy consumption.
AI searches for new hormones in 20,000 human genes
To speed up the research, scientists created a computer algorithm called Peptide Predictor. Instead of physically isolating and examining hundreds of thousands of peptides, the program analyzed the approximately 20,000 human protein-coding genes, looking for sequences in which the enzyme was likely to make cuts.
The team then refined the results by focusing on genes associated with proteins released outside cells, a common feature of hormones. They also required that each candidate protein contain at least four potential cutting sites.
These filters narrowed down a huge collection of possibilities to 373 prohormones, making experimental testing much more practical.
“The algorithm was absolutely essential to our findings,” Svensson said.
Peptide Predictor estimated that the enzyme could produce 2,683 distinct peptides from these 373 proteins. From this collection, Svensson and Coassolo selected candidates that seemed particularly likely to influence brain activity.
The researchers ultimately tested 100 peptides, including GLP-1, using nerve cells grown in the laboratory. Their goal was to find substances that could stimulate neuronal activity, the first indication that a peptide could influence important brain processes.
A small peptide produces a surprising result
GLP-1 performed well in laboratory tests, increasing neuronal activity up to three times the level seen in untreated control cells.
However, a previously unknown peptide produced an even more striking response. Composed of only 12 amino acids, it increased neuronal activity tenfold compared to controls.
The researchers named the molecule BRP after the larger protein from which it is derived, BPM/retinoic acid-inducible neuronal specificity 2, or BRINP2 (BRINP2-related peptide).
This unusually powerful response made BRP a promising candidate for further investigation. The next question was whether stimulating brain cells grown in the laboratory would result in significant changes in the appetite and body weight of living animals.
Food consumption decreases by up to 50% in animal experiments
The team tested BRP in lean mice and minipigs (which more closely reflect human metabolism and eating habits than mice). Before the animals were fed, the researchers administered BRP by injection into the muscle.
The results were striking. Over the next hour, treated animals consumed up to 50% less food than expected, suggesting that BRP could strongly influence hunger.
The scientists then examined whether repeated treatment could produce lasting changes in body weight. Obese mice received daily BRP injections for 14 days. At the end of the experiment, the treated mice had lost an average of 3 grams, while the untreated control mice had gained about 3 grams.
Importantly, almost all of the weight lost by the BRP-treated mice came from body fat rather than muscle. Muscle preservation is an important goal of obesity treatment because muscle tissue supports strength, mobility, and metabolic health.
Treated animals also showed improvements in glucose and insulin tolerance. These measurements reflect how effectively the body handles sugar and responds to insulin, the hormone that helps move glucose from the bloodstream into cells.
Together, the results suggest that BRP could influence both appetite and metabolic health, although it remains unknown whether people would experience comparable benefits.
Could BRP avoid common side effects of Ozempic?
One of the most intriguing aspects of this finding is the possibility that BRP could provide weight loss benefits while avoiding some of the side effects associated with semaglutide and similar drugs.
To study potential side effects, researchers monitored the behavior and physical responses of treated mice and pigs. They found no significant differences in movement, water consumption, anxiety-related behavior, or fecal production compared to control animals.
The lack of changes in fecal output was particularly interesting because constipation is a known side effect of medications such as Ozempic. Experiments also showed that BRP promoted fat loss without the substantial muscle loss that can accompany some weight reduction treatments.
Nausea is another common concern with existing GLP-1 drugs, although animal experiments cannot fully determine whether BRP would prevent this symptom in humans. Human testing will be essential to determine the true side effect profile of the molecule.
Additional investigations into brain activity and other physiological responses reinforced the idea that BRP acts differently from semaglutide. The peptide activated distinct neuronal and metabolic pathways rather than simply copying the effects of GLP-1.
This difference may explain why the researchers observed strong appetite suppression without many of the behavioral and digestive changes they were monitoring.
What’s next for the potential alternative to Ozempic?
Despite the encouraging results, BRP is still at an early stage of development. Researchers need to better understand exactly how the molecule communicates with cells and what its effects might be…
Gn Health
