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. This groundbreaking discovery, detailed in the prestigious journal Nature, holds significant promise for addressing the global obesity epidemic, a complex health crisis affecting billions worldwide.
The newly identified molecule, dubbed BRP (BRINP2-related-peptide), operates through a distinct yet related metabolic pathway compared to semaglutide, activating a separate group of neurons within the brain. This crucial difference could position BRP as a more precise and potentially safer tool for managing appetite and body weight, minimizing the undesirable side effects often associated with current treatments.
A More Targeted Approach to Appetite Regulation
The significance of BRP’s targeted action was highlighted by Katrin Svensson, PhD, an assistant professor of pathology at Stanford Medicine and senior author of the study. "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," explained Dr. Svensson. "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 but vital region nestled deep within the brain, serves as the body’s central command for numerous critical functions, including the regulation of hunger, body temperature, hormone activity, and energy expenditure. By concentrating its effects primarily in this area, BRP offers the potential to influence appetite and metabolic processes without eliciting the broad systemic responses that can lead to adverse reactions in other parts of the body.
Driven by the profound implications of their findings, Dr. Svensson has co-founded a company poised to advance BRP into human clinical trials in the near future. This expedited transition underscores the urgency and optimism surrounding the molecule’s therapeutic potential. Laetitia Coassolo, PhD, a senior research scientist at Stanford and lead author of the study, emphasized the collaborative effort that underpinned this discovery, which also involved researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia.
Artificial Intelligence as a Catalyst for Discovery
The breakthrough in identifying BRP was heavily reliant on the sophisticated application of artificial intelligence (AI). This advanced computational power enabled researchers to systematically sift through vast datasets of proteins, specifically those belonging to the class known as prohormones.
Prohormones are essentially inactive precursor molecules that require enzymatic cleavage to become biologically active peptides, which then function as hormones. These peptides act as crucial messengers, transmitting signals that govern a wide array of physiological processes, including metabolism and appetite regulation, within the brain and across the entire body.
The complexity of prohormone processing lies in the fact that a single prohormone can be cleaved in multiple ways, yielding a diverse array of peptides. Identifying the genuinely functional peptide hormones among the multitude of fragments produced during normal protein turnover is a formidable challenge. Traditional laboratory techniques, while capable of isolating and identifying peptides, can generate enormous volumes of data, necessitating the painstaking manual examination of hundreds of thousands of molecules to pinpoint those with significant biological effects.
Charting New Metabolic Signals with Precision
The Stanford team strategically focused their investigation on an enzyme known as prohormone convertase 1/3 (PC1/3). This enzyme plays a critical role in cleaving prohormones at specific amino acid sequences and has previously been implicated in human obesity, making it a prime target for understanding metabolic dysregulation.
A well-established peptide produced through the action of PC1/3 is glucagon-like peptide 1 (GLP-1), a hormone instrumental in regulating hunger and blood sugar levels. Semaglutide, a widely recognized weight-loss medication, mimics the effects of GLP-1 in the body. Building on this knowledge, the researchers hypothesized that PC1/3 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 AI.
Peptide Predictor: An AI-Driven Analytical Tool
Instead of relying on time-consuming traditional methods of extracting proteins and peptides from tissues followed by mass spectrometry, the researchers developed a novel computer algorithm named "Peptide Predictor." This innovative program was designed to scan all 20,000 human protein-coding genes, searching for the characteristic sites where prohormone convertases, like PC1/3, typically cleave proteins.
The AI’s search was further refined by focusing on genes that produce proteins secreted outside the cell – a common characteristic of hormones – and that contained at least four potential cleavage sites. This rigorous filtering process dramatically narrowed the scope of investigation from thousands of genes to a more manageable 373 prohormones. "The algorithm was absolutely key to our findings," Dr. Svensson stated, underscoring its indispensable role in the discovery process.
Peptide Predictor further estimated that PC1/3 could generate an impressive 2,683 distinct peptides from these 373 prohormones. Dr. Coassolo and Dr. Svensson then strategically prioritized sequences that showed the highest likelihood of impacting brain function. They selected 100 peptides, including GLP-1, for experimental testing, assessing their ability to stimulate neuron-like cells cultured in the laboratory.
A Small Peptide with a Profound Impact
As anticipated, GLP-1 demonstrated a potent ability to activate the neuronal cells, increasing their activity by threefold compared to untreated control cells. However, a much smaller peptide, comprising only 12 amino acids, elicited an even more dramatic response. This peptide, subsequently named BRP, boosted neuronal activity by a remarkable tenfold increase over controls.
The parent prohormone for BRP was identified as BPM/retinoic acid inducible neural specific 2, or BRINP2. Amino acids, the fundamental building blocks of proteins and peptides, are incredibly small. The fact that a molecule composed of just 12 amino acids could exert such a powerful influence was a significant revelation, especially when contrasted with the larger size of most full-length proteins.
Promising Preclinical Results in Animal Models
The researchers extended their investigation to assess BRP’s effects in both lean mice and minipigs. Minipigs were chosen due to their metabolic and eating patterns, which more closely mirror those of humans than mice. In these studies, an intramuscular injection of BRP administered prior to feeding led to a substantial reduction in food intake, decreasing it by up to 50% within the subsequent hour in both species.
Further experiments involved administering daily BRP injections to obese mice over a 14-day period. The results were compelling: treated animals experienced an average weight loss of 3 grams, with the reduction primarily attributed to a decrease in body fat. In stark contrast, mice in the control group gained approximately 3 grams during the same timeframe.
Beyond weight management, the treated obese mice also exhibited improvements in glucose and insulin tolerance. These metabolic markers are critical indicators of how effectively the body regulates blood sugar and responds to insulin, the hormone responsible for facilitating glucose uptake into cells.
Mitigating Side Effects: A Key Advantage
Crucially, behavioral testing revealed no significant differences between BRP-treated and untreated animals in parameters such as movement, water consumption, anxiety-like behavior, or fecal production. The absence of any impact on fecal production is particularly noteworthy, as semaglutide is known to slow digestion and can lead to constipation. Moreover, the researchers observed no signs of nausea-related responses or the substantial muscle loss that has been associated with some existing weight-loss therapies.
Additional physiological assessments confirmed that BRP operates through distinct metabolic and neuronal pathways compared to those activated by GLP-1 or semaglutide. These findings strongly suggest that BRP may achieve appetite suppression through a more focused biological route, offering a potential advantage in terms of tolerability and safety, although these results are currently limited to animal models.
Navigating the Path to Human Trials
The Stanford team is now actively engaged in identifying the specific cell-surface receptors to which BRP binds. Receptors are molecular docking sites that receive signals from hormones, drugs, and other chemical messengers. Pinpointing BRP’s target receptor will be instrumental in elucidating the precise mechanisms by which this peptide influences appetite and metabolism.
Furthermore, researchers aim to meticulously map the complete cascade of events that unfold after BRP binds to its intended receptor. Another significant consideration is the duration of BRP’s action. Small peptides are often rapidly metabolized and cleared by the body, potentially limiting their therapeutic window. The research team is exploring strategies to enhance BRP’s stability and prolong its effects, aiming to facilitate a more practical dosing schedule for future human applications.
The global burden of obesity has been a persistent challenge for decades, with a notable lack of highly effective pharmacological interventions. "The lack of effective drugs to treat obesity in humans has been a problem for decades," Dr. Svensson remarked. "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 research was supported by substantial funding from 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. Dr. Svensson also holds a co-founder role at Merrifield Therapeutics, indicating the direct commercialization efforts underway to bring this promising discovery to patients. The scientific community eagerly awaits the forthcoming human clinical trials, which hold the potential to usher in a new era of obesity treatment characterized by enhanced efficacy and improved safety profiles.
