Researchers from Stanford Medicine have discovered a naturally occurring molecule that may help curb appetite and facilitate weight loss, acting similarly to semaglutide, the active agent in Ozempic. Animal studies indicate this molecule, named BRP, might avoid common side effects linked to semaglutide, such as nausea, constipation, and significant muscle loss.
BRP engages a distinct metabolic pathway and activates a different set of neurons in the brain. This separation suggests it could provide a more targeted approach to managing appetite and weight.
A Targeted Solution for Weight Management
Assistant professor of pathology, Dr. Katrin Svensson, explains, “Semaglutide targets receptors in various areas, including the brain, gut, and pancreas. This widespread effect results in slower food digestion and reduced blood sugar. In comparison, BRP primarily influences the hypothalamus, which is responsible for regulating hunger and metabolism.”
The hypothalamus, a small area deep within the brain, plays a critical role in controlling hunger, body temperature, hormone release, and energy expenditure. Since BRP predominantly works in this region, it may regulate appetite with fewer effects elsewhere in the body.
Dr. Svensson has co-founded a company set to initiate clinical trials of BRP in humans soon. She is the senior author of the research, which was published in Nature.
Harnessing Artificial Intelligence for Discovery
The identification of BRP heavily relied on artificial intelligence, which enabled the team to analyze proteins from a group known as prohormones.
Prohormones are inactive precursors that require enzymatic modification to become functional peptides. These peptides can act as hormones, conveying signals that affect metabolism and appetite in the brain and body.
One such enzyme, prohormone convertase 1/3, facilitated this research. It cleaves prohormones at specific sequences and has been associated with obesity.
The researchers speculated that this enzyme might yield other peptides impacting energy balance and appetite, prompting them to employ AI for exploration.
Introducing Peptide Predictor
Instead of the traditional method of manually isolating proteins and peptides for analysis, the researchers developed an algorithm called Peptide Predictor. This tool scanned all 20,000 human protein-coding genes to identify potential cleavage sites for prohormone convertases. They narrowed it down to genes that produced secreted proteins possessing at least four cleavage sites, ultimately identifying 373 prohormones for further study.
“The algorithm was crucial to our success,” noted Svensson.
Peptide Predictor estimated that the targeted enzyme could create 2,683 unique peptides from the selected proteins. Coassolo and Svensson then focused on sequences likely to influence neuronal activity, selecting 100 peptides, including GLP-1, for laboratory testing.
A Tiny Yet Powerful Peptide
The researchers observed that GLP-1 significantly increased neuronal activity, tripling it compared to untreated cells. However, a smaller peptide made up of just 12 amino acids produced an even more pronounced effect, boosting neuronal activity tenfold compared to controls.
They named this potent peptide BRP, derived from its parent prohormone, BPM/retinoic acid-inducible neural specific 2 (BRINP2).
Testing BRP's Effectiveness
Further studies involved administering BRP to lean mice and minipigs, which provide a more accurate representation of human metabolic responses. An injection of BRP before meals led to a reduction in food intake by up to 50% in both species.
In a separate experiment, obese mice receiving daily BRP injections for two weeks lost an average of 3 grams, primarily from body fat, while control mice gained weight. The treated subjects also exhibited improved glucose and insulin tolerance, key indicators of metabolic health.
Lack of Common Side Effects
Behavioral assessments revealed no significant differences in mobility, water intake, anxiety-like behavior, or fecal output between BRP-treated and untreated animals. This is noteworthy because semaglutide often induces constipation and nausea, which were absent in this study. Additionally, BRP appeared to operate through different metabolic and neuronal pathways than GLP-1 or semaglutide.
Next Steps Before Human Trials
The research team is currently focused on identifying the cell-surface receptors that interact with BRP. Understanding the receptor it binds to will clarify how the peptide alters appetite and metabolism. They also aim to outline the sequence of events triggered by BRP binding.
One challenge remains the stability of small peptides in the body, which can affect their efficacy. Researchers are exploring strategies to prolong BRP’s lifespan, enhancing its potential use in humans.
Dr. Svensson commented on the ongoing challenges in obesity treatment, stating, “The lack of effective weight loss drugs has persisted for years. Nothing we've previously tested has matched semaglutide's ability to reduce appetite and body weight, and we are keen to determine BRP's safety and effectiveness in humans.”
Researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia also contributed to this study. Funding sources included various National Institutes of Health grants, the SPARK Translational Research Program at Stanford, and other organizations. Both Svensson and Coassolo hold patents associated with BRP peptides intended for metabolic disorders, with Svensson co-founding Merrifield Therapeutics.
