Stanford Medicine researchers have identified a naturally occurring molecule that may suppress appetite and reduce body weight in a way that resembles semaglutide, the active ingredient in Ozempic. In animal studies, the molecule also appeared to avoid several problems associated with the drug, including nausea, constipation and substantial muscle loss.
The molecule, known as BRP, works through a different but related metabolic pathway and activates a separate group of neurons in the brain. That distinction could make it a more precise tool for controlling appetite and body weight, potentially offering a new avenue in the ongoing global challenge of addressing obesity and metabolic disorders. This discovery, published on March 5th in the prestigious journal Nature, represents a significant leap forward in understanding the intricate mechanisms that regulate appetite and metabolism.
A More Targeted Approach to Appetite Control
Assistant Professor of Pathology Katrin Svensson, PhD, a senior author on the study, explained the fundamental difference between BRP and existing medications like semaglutide. "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," Dr. Svensson stated. "That’s why Ozempic has widespread 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."
The hypothalamus, a small yet vital region deep within the brain, serves as the body’s central command for numerous critical functions, including regulating hunger, body temperature, hormone activity, and energy utilization. The apparent localized action of BRP within this area suggests a potential for influencing appetite and promoting weight loss with a reduced risk of the systemic side effects that have been a concern for some patients using current treatments. This targeted mechanism could herald an era of more personalized and well-tolerated weight management therapies.
Dr. Svensson has co-founded a company with the intention of initiating clinical trials of BRP in humans in the near future, a move that underscores the preclinical promise of this novel molecule. Senior Research Scientist Laetitia Coassolo, PhD, is the lead author of the study, spearheading the intensive laboratory work that led to this groundbreaking discovery.
Artificial Intelligence Reveals Hidden Peptides
The genesis of this significant finding was heavily reliant on the sophisticated application of artificial intelligence (AI). This advanced technology enabled the researchers to meticulously search through a vast and complex landscape of proteins, specifically focusing on a group known as prohormones.
Prohormones are essentially inactive precursor molecules. They do not exhibit their final biological functions until they undergo enzymatic cleavage, a process where enzymes break them down into smaller fragments called peptides. Some of these resultant peptides then embark on crucial roles as hormones, acting as signaling molecules that influence a wide array of complex processes in the brain and throughout the body, including metabolism and appetite regulation.
A single prohormone can be cleaved in multiple ways, leading to the generation of numerous potential peptides. Identifying the specific peptides that are biologically significant presents a considerable challenge. This difficulty arises because genuine peptide hormones are relatively rare and can easily be obscured within the large quantities of ordinary fragments produced during normal protein processing and degradation.
While traditional laboratory methods are capable of isolating and identifying peptides, the process can be exceptionally data-intensive. Researchers may find themselves sifting through hundreds of thousands of molecules in pursuit of the few that exert meaningful biological effects. This laborious process often necessitates significant time and resources.
Searching for New Metabolic Signals
The research team strategically concentrated their efforts on an enzyme identified as prohormone convertase 1/3. This specific enzyme is known to cleave prohormones at particular amino acid sequences and has a documented association with obesity in human populations. This prior link provided a compelling rationale for its inclusion in the investigation.
One of the well-established peptides produced through the action of prohormone convertase 1/3 is glucagon-like peptide 1, or GLP-1. GLP-1 plays a critical role in regulating hunger and blood sugar levels, and it is precisely these effects that semaglutide mimics in the body. Building upon this knowledge, the researchers hypothesized that the same enzyme might also be responsible for generating other peptides that influence energy balance and appetite. To uncover these hidden signals, they turned to the power of artificial intelligence.
Peptide Predictor: An AI-Powered Discovery Tool
Instead of relying on the time-consuming and often inefficient process of manually extracting proteins and peptides from tissues followed by analysis using techniques such as mass spectrometry, the researchers developed a sophisticated computer algorithm. This innovative program, christened "Peptide Predictor," was designed to revolutionize the peptide discovery process.
The algorithm systematically scanned all 20,000 human protein-coding genes. Its objective was to identify the specific types of sites where prohormone convertases, like prohormone convertase 1/3, typically cleave proteins. The search was further refined by focusing on genes that produce proteins secreted outside the cell, a common characteristic of hormones, and those containing at least four potential cleavage sites. This rigorous filtering process dramatically narrowed the field of investigation from tens of thousands of genes to a more manageable group of 373 prohormones.
"The algorithm was absolutely key to our findings," Dr. Svensson emphasized, highlighting the indispensable role of AI in their breakthrough.
Peptide Predictor then went on to estimate that prohormone convertase 1/3 could generate an astonishing 2,683 distinct peptides from these 373 precursor proteins. From this extensive list, Dr. Coassolo and Dr. Svensson strategically focused on sequences that demonstrated the highest likelihood of impacting brain function. They selected 100 peptides, including the already known GLP-1, and subjected them to rigorous laboratory testing to determine if they could stimulate neuron-like cells cultured in vitro.
A Tiny Peptide With an Outsized Effect
As anticipated, GLP-1 exhibited a strong stimulatory effect on the neuronal cells, significantly increasing their activity to three times the level observed in untreated control cells. However, it was a much smaller peptide that produced an even more dramatic and surprising response. This peptide, composed of a mere 12 amino acids, triggered a tenfold increase in neuronal activity compared to the controls, far exceeding the effect of GLP-1.
The researchers subsequently named this potent peptide BRP, a designation derived from its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2 (BRINP2-related-peptide). Amino acids are the fundamental building blocks of all proteins and peptides. A molecule comprising only 12 amino acids is remarkably small, especially when contrasted with most full-sized proteins. Yet, BRP demonstrated an exceptionally potent effect in these initial cellular assays, hinting at its significant biological potential.
Animal Studies Reveal Significant Appetite Suppression and Weight Loss
The promising results from the cell-based assays prompted the researchers to move to in vivo studies. They tested BRP in both lean mice and minipigs. Minipigs were chosen because their metabolic and eating patterns more closely mirror those of humans than mice do, providing a more relevant model for preclinical evaluation.
An intramuscular injection of BRP administered prior to feeding resulted in a remarkable reduction in food intake. Over the following hour, both species consumed up to 50% less food compared to their untreated counterparts. This immediate and substantial impact on appetite was a significant indicator of BRP’s potential efficacy.
The research team then embarked on a longer-term study involving obese mice. For a period of 14 days, these mice received daily BRP injections. The results were striking: on average, the treated animals lost 3 grams, with the vast majority of this weight loss attributed to a reduction in body fat. In contrast, the control group of mice experienced a weight gain of approximately 3 grams during the same timeframe. This demonstrates not only appetite suppression but also a tangible and significant impact on body composition.
Beyond weight loss, the treated mice also exhibited improved glucose and insulin tolerance. These metabolic markers are critical indicators of how effectively the body regulates blood sugar and responds to insulin, the hormone essential for facilitating glucose uptake from the bloodstream into cells. Improved glucose and insulin tolerance suggest a positive impact on overall metabolic health, a crucial consideration in the management of obesity and related conditions like type 2 diabetes.
Absence of Common Side Effects Marks a Key Distinction
A particularly encouraging aspect of the BRP studies was the apparent lack of common side effects associated with existing weight loss medications. Behavioral testing revealed no meaningful differences between the BRP-treated animals and the control groups in terms of movement, water consumption, anxiety-like behaviors, or fecal production.
The absence of changes in fecal production was especially noteworthy. Semaglutide, while effective, is known to slow digestion, which can lead to constipation in some individuals. The researchers also did not observe any nausea-related responses, a common gastrointestinal side effect reported with GLP-1 receptor agonists, nor did they detect substantial muscle loss, another concern associated with rapid weight loss achieved through some therapeutic interventions.
Further analyses of brain activity and body function confirmed that BRP operates through distinct metabolic and neuronal pathways compared to those activated by GLP-1 or semaglutide. This mechanistic divergence is crucial because it suggests that BRP may achieve its appetite-suppressing effects via a more focused biological route. While these findings are currently limited to animal models, they provide a strong foundation for optimism regarding BRP’s potential therapeutic profile in humans.
Navigating the Path to Human Testing and Future Implications
The researchers are now actively engaged in the critical next steps necessary to advance BRP towards human clinical trials. A primary focus is identifying the specific cell-surface receptors to which BRP binds. Receptors are essential molecular structures that act as docking stations for hormones, drugs, and other chemical messengers, initiating cellular responses. Understanding which receptor BRP targets will provide invaluable insights into the precise mechanisms by which it influences appetite and metabolism.
Equally important is the endeavor to map the complete cascade of events that transpires after BRP successfully binds to its target receptor. This detailed understanding of the molecular signaling pathway is essential for predicting potential efficacy and safety in humans.
Another significant challenge lies in determining the duration of BRP’s action in the body. Small peptides are often rapidly broken down by metabolic enzymes, which can limit their therapeutic window. The research team is actively investigating strategies to enhance BRP’s stability and prolong its effects. This would pave the way for more practical dosing schedules if the molecule proves effective in human trials.
"The lack of effective drugs to treat obesity in humans has been a problem for decades," Dr. Svensson commented, underscoring the significant unmet medical need in this area. "Nothing we’ve tested before has compared to semaglutide’s ability to decrease appetite and body weight. We are very eager to learn if it is safe and effective in humans."
The potential implications of this research extend far beyond individual weight management. Obesity is a complex global health crisis, contributing to a myriad of comorbidities including cardiovascular disease, type 2 diabetes, certain cancers, and joint problems. An effective, well-tolerated pharmacological agent that targets appetite and promotes fat loss could revolutionize the treatment landscape for these conditions, leading to improved public health outcomes and reduced healthcare burdens worldwide.
The collaborative nature of this research is also noteworthy, with contributions from researchers at the University of California, Berkeley; the University of Minnesota; and the University of British Columbia, underscoring the interdisciplinary effort required to tackle such complex biological questions. Funding for this groundbreaking work was provided by several prestigious institutions, including the National Institutes of Health (grants R01DK125260, P30DK116074, K99AR081618 and GM113854), the SPARK Translational Research Program at Stanford, Stanford Bio-X, the Stanford Maternal and Child Health Research Institute, the American Heart Association, a Stanford Medicine Dean’s Fellowship Award, the Carlsberg Foundation, and the Wu Tsai Human Performance Alliance. Dr. Svensson and Dr. Coassolo are listed as inventors on patents pertaining to BRP peptides for metabolic disorders, and Dr. Svensson is a co-founder of Merrifield Therapeutics, signaling a clear commitment to translating these scientific discoveries into tangible therapeutic solutions.
