Scientists at Stanford Medicine have identified a naturally occurring 12-amino-acid molecule that reduced food intake and body fat in early animal studies. Known as BRP, the peptide appears to act selectively in the hypothalamus, a brain region involved in hunger and metabolism. The findings suggest that BRP could eventually lead to weight-loss treatments with fewer digestive and muscle-related side effects than semaglutide-based drugs such as Ozempic, although its safety and effectiveness in humans remain unknown.
A different approach to weight loss
BRP appears to work differently from existing treatments. Rather than affecting receptors in multiple organs, it seems to act primarily on brain cells involved in appetite and metabolic regulation. This more targeted activity could potentially suppress hunger while reducing problems such as nausea, constipation and significant muscle loss.
“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, an 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 within the brain that helps regulate hunger, energy use, body temperature and other functions needed to maintain the body’s internal balance. Because of its central role in appetite, it has become an important target for obesity researchers.
Semaglutide works by mimicking glucagon-like peptide 1, or GLP-1, a hormone that helps regulate blood sugar and sends signals related to hunger and fullness. GLP-1 receptors are distributed throughout several parts of the body, which helps explain why drugs that activate them can produce effects beyond appetite suppression.
BRP appears to influence some of the same broad metabolic functions as semaglutide but activates a different population of brain cells. Researchers believe this distinction could allow more precise control of hunger while limiting effects on other tissues.
Using artificial intelligence to search for new hormones
Finding BRP required the researchers to address a longstanding challenge in hormone discovery. 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 therefore 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 become chemical messengers that regulate 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 are biologically active and which are simply byproducts of normal protein processing. Potentially important peptide hormones are relatively rare compared with the much larger collection of ordinary protein fragments.
Traditional methods often involve extracting proteins from biological tissues and analyzing them with techniques such as mass spectrometry. These methods identify molecules using properties related to their mass, but the enormous number of possible peptides makes the search for new hormones challenging.
The Stanford team took a different approach. They focused on prohormone convertase 1/3, an enzyme that cuts prohormones at specific amino-acid sequences. The enzyme 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.
One hormone produced through this process is GLP-1, the hormone mimicked by semaglutide. The researchers reasoned that other peptides created through similar processing might also regulate appetite and energy use.
To accelerate the search, the scientists created a computer algorithm called Peptide Predictor. Instead of isolating and testing hundreds of thousands of peptides, the program analyzed approximately 20,000 genes that code for human proteins. It looked for sequences likely to be cut by prohormone convertase 1/3.
The team then concentrated on genes associated with proteins released outside cells, a common characteristic of hormones. Each candidate protein also had to contain at least four potential enzyme-cutting 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 Coassolo then selected candidates they considered especially likely to influence brain activity.
The researchers tested 100 peptides, including GLP-1, using nerve cells grown in the laboratory. They were looking for substances that stimulated neuronal activity, an early indication that the peptides might affect important brain processes.
A 12-amino-acid peptide produces a strong response
GLP-1 increased neural activity threefold compared with untreated control cells. However, one previously unrecognized peptide produced an even stronger response. 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, making BRP short for BRINP2-related peptide.
The unusually strong cellular response made BRP a promising candidate for further investigation. The researchers next examined whether stimulating brain cells in the laboratory would translate into changes in appetite and body weight in living animals.
Food intake fell by up to 50% in animal studies
The team tested BRP in lean mice and minipigs, which more closely reflect human metabolism and dietary patterns than mice do. The animals received BRP through an intramuscular injection before being given food.
During the following hour, treated animals ate up to 50% less food than expected, suggesting that BRP can strongly affect hunger.
The researchers then examined whether repeated treatment produced lasting changes in weight. Obese mice received daily BRP injections for 14 days. By the end of the experiment, the treated mice had lost an average of 3 grams, while untreated control mice had gained approximately 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 results suggest that BRP can influence both appetite and metabolic health. However, it remains unclear whether people would experience comparable effects.
Potentially fewer digestive side effects
Another notable aspect of the findings is the possibility that BRP could provide weight-loss benefits without some of the unwanted effects associated with semaglutide and similar drugs.
To investigate possible 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 prevents nausea in humans. Human trials will be essential for determining the molecule’s actual side-effect profile.
Additional studies of brain activity and other physiological responses strengthened the idea that BRP works differently from semaglutide. Rather than simply copying GLP-1’s effects, the peptide activated different neural and metabolic pathways. This difference may explain why it produced strong appetite suppression without some of the behavioral and digestive changes observed with other treatments.
What comes next
BRP remains in the early stages of development. Researchers still need to determine precisely how it communicates with cells and how long its effects persist.
One priority is identifying the cell-surface receptor that recognizes BRP. Receptors are specialized proteins that respond to specific chemical signals, allowing cells to detect messages and trigger biological responses. Identifying BRP’s receptor could help explain how the peptide affects hunger and metabolism.
The team also wants to investigate ways to extend BRP’s activity in the body. Peptides break down relatively quickly and may require frequent injections. A longer-lasting version could make treatment more convenient if BRP ultimately proves effective in people.
The central challenge is determining whether the apparent benefits seen in animals translate into meaningful benefits for patients. Before BRP could become an obesity treatment, clinical trials would need to evaluate its safety, effectiveness, appropriate dosage and potential side effects.
“The lack of effective drugs to treat human obesity 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.”
Research collaborators and funding
Researchers from the University of California, Berkeley, the University of Minnesota and the University of British Columbia also participated in the study.
The work was supported by 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 Coassolo 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