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 discovery, powered by advanced artificial intelligence, offers a promising new avenue in the ongoing quest for effective obesity treatments.
A New Hope in the Fight Against Obesity
The global obesity epidemic continues to pose a significant public health challenge, with rates steadily climbing worldwide. While medications like semaglutide have demonstrated remarkable efficacy in promoting weight loss and improving metabolic health for many, their widespread use is often tempered by a spectrum of gastrointestinal side effects and concerns about muscle mass reduction. This has fueled a persistent search for alternative therapeutic strategies that can achieve similar weight management benefits with an improved safety and tolerability profile.
The molecule, provisionally named BRP (BRINP2-related-peptide), emerges from this critical need. It operates through a distinct, albeit related, metabolic pathway compared to semaglutide, activating a separate set of neurons in the brain. This fundamental difference is key to its potential as a more precise instrument for modulating appetite and body weight.
Targeting the Brain’s Appetite Control Center
"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," explained Katrin Svensson, PhD, an assistant professor of pathology at Stanford Medicine and senior author of the study. "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 master regulator of fundamental bodily functions, including hunger, thirst, body temperature, hormone activity, and energy expenditure. By seemingly concentrating its action within this critical area, BRP holds the potential to influence appetite and metabolism without eliciting the broad range of systemic effects often observed with drugs acting on more widely distributed receptors. This targeted action could translate into a significantly better patient experience, minimizing the discomfort and adverse events that can hinder long-term adherence to weight management therapies.
Dr. Svensson has taken a proactive step in translating this groundbreaking research into clinical reality, co-founding a company poised to initiate human clinical trials in the near future. This rapid progression from laboratory discovery to potential human application underscores the significant promise and perceived potential of BRP.
The research detailing the discovery and initial characterization of BRP was published on March 5th in the prestigious scientific journal Nature. Dr. Laetitia Coassolo, a senior research scientist at Stanford Medicine, is the lead author of this seminal study.
The Power of Artificial Intelligence in Unveiling Hidden Peptides
The identification of BRP was not a matter of chance but a testament to the innovative application of artificial intelligence (AI) in biological research. The research team leveraged AI to navigate the complex landscape of proteins, specifically focusing on a class known as prohormones.
Prohormones are essentially inactive precursor molecules. They lie dormant until specific enzymes cleave them into smaller, biologically active fragments known as peptides. These peptides then function as signaling molecules, carrying crucial messages that influence a myriad of physiological processes, including metabolism, appetite regulation, and a host of other complex functions within the brain and throughout the body.
The challenge lies in the sheer combinatorial complexity. A single prohormone can be processed in multiple ways, yielding a vast array of potential peptides. Distinguishing the truly biologically significant peptide hormones from the numerous ordinary fragments generated during normal protein turnover is an arduous task. Traditional laboratory methods, while capable of isolating and identifying peptides, can generate overwhelming quantities of data, requiring researchers to meticulously sift through hundreds of thousands of molecular candidates to pinpoint those with meaningful physiological effects.
Strategic Pursuit of Novel Metabolic Signals
The Stanford team strategically focused their investigation on an enzyme called prohormone convertase 1/3 (PC1/3). This enzyme is known for its specific role in cleaving prohormones at particular amino acid sequences. Importantly, PC1/3 has previously been implicated in human obesity, making it a compelling target for exploring novel appetite-regulating peptides.
One of the well-established peptides produced by PC1/3 is glucagon-like peptide 1 (GLP-1). GLP-1 plays a critical role in regulating hunger and blood sugar levels, and it forms the basis for the action of semaglutide and other similar drugs. Building on this knowledge, the researchers hypothesized that PC1/3 might also be responsible for generating other peptides with a significant influence on energy balance and appetite. To systematically explore this possibility, they turned to the sophisticated capabilities of AI.
Peptide Predictor: An AI-Driven Discovery Engine
Instead of relying on conventional, labor-intensive methods of extracting proteins and peptides from tissues followed by time-consuming mass spectrometry analysis, the researchers developed a novel computer algorithm they christened "Peptide Predictor." This AI-powered tool was designed to efficiently scan the human genome for potential peptide precursors.
The algorithm systematically analyzed all approximately 20,000 human protein-coding genes, searching for the specific types of recognition sites where prohormone convertases, like PC1/3, typically cleave proteins. The initial 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 down the field of investigation from tens of thousands of genes to a more manageable 373 prohormones.
"The algorithm was absolutely key to our findings," stated Dr. Svensson, emphasizing the indispensable role of AI in their breakthrough.
Peptide Predictor then estimated that PC1/3 could potentially generate an astonishing 2,683 distinct peptides from these 373 prohormones. Dr. Coassolo and Dr. Svensson subsequently focused their attention on sequences that exhibited a higher likelihood of impacting brain function, given the central role of the brain in appetite regulation.
From this refined list, they selected 100 peptides, including the known player GLP-1, and subjected them to laboratory testing. The critical step involved assessing whether these selected peptides could stimulate neuron-like cells cultured in vitro.
A Small Peptide with a Monumental Impact
As anticipated, GLP-1 demonstrated robust activity, significantly activating the neuronal cells and increasing their activity by a factor of three compared to untreated control cells. However, a much smaller peptide, BRP, produced an even more striking response. Composed of only 12 amino acids, BRP amplified neuronal activity by a remarkable tenfold increase relative to the controls.
The researchers christened this potent peptide BRP, deriving its name from its parent prohormone, BPM/retinoic acid inducible neural specific 2 (BRINP2). Amino acids are the fundamental building blocks of proteins and peptides. A molecule as minuscule as BRP, comprising just 12 amino acids, is exceptionally small when compared to most full-length proteins. Yet, its profound effect in initial cell-based assays highlighted its significant biological potential.
Pre-clinical Efficacy: Substantial Food Intake Reduction and Weight Loss
The promising results from cell cultures prompted the researchers to advance their investigation into animal models. They tested BRP in both lean mice and, crucially, in minipigs. Minipigs were chosen for their physiological similarities to humans in terms of metabolism and eating patterns, offering a more relevant pre-clinical model than mice alone.
In these studies, an intramuscular injection of BRP administered shortly before feeding resulted in a significant reduction in food intake, with intake falling by as much as 50% within the hour following the injection in both species.
Further demonstrating its weight-management potential, daily BRP injections were administered to obese mice over a 14-day period. The treated animals exhibited an average weight loss of 3 grams, with the overwhelming majority of this reduction attributed to body fat loss. In stark contrast, control mice in the same study experienced an average weight gain of approximately 3 grams over the same duration.
Beyond weight loss, the BRP-treated obese mice also showed improvements in glucose and insulin tolerance. These metabolic markers are crucial indicators of the body’s ability to efficiently regulate blood sugar and respond to insulin, a hormone vital for glucose uptake by cells. Improved glucose and insulin tolerance suggest a positive impact on overall metabolic health, a key benefit sought in obesity interventions.
A Favorable Side Effect Profile in Animal Models
A particularly encouraging aspect of the pre-clinical findings was the absence of several common side effects associated with existing weight loss medications. Behavioral assessments in the treated animals revealed no meaningful differences in movement, water consumption, anxiety-like behaviors, or fecal production when compared to their untreated counterparts.
The lack of impact on fecal production is especially noteworthy, given that semaglutide is known to slow digestion and can lead to constipation. Furthermore, the researchers did not observe any behavioral indicators of nausea or signs of substantial muscle loss, adverse events that have been reported with some current weight-loss treatments.
Additional analyses of brain activity and overall body function provided further evidence that BRP operates through distinct metabolic and neuronal pathways compared to those activated by GLP-1 or semaglutide. These findings strengthen the hypothesis that BRP may exert its appetite-suppressing effects via a more focused biological route, though it is important to reiterate that these observations are currently limited to animal studies.
Charting the Path to Human Trials
With the promising pre-clinical data in hand, the Stanford Medicine team is now focused on the critical next steps toward human application. A primary objective is to identify the specific cell-surface receptors to which BRP binds. Receptors act as molecular docking stations, receiving signals from hormones, drugs, and other chemical messengers. Understanding BRP’s precise receptor interaction will be crucial for elucidating the exact mechanisms by which it influences appetite and metabolism.
The researchers also aim to map the complete cascade of events that unfolds after BRP binds to its target receptor. This detailed understanding will be vital for predicting and managing potential downstream effects.
Another significant challenge lies in addressing the duration of BRP’s action. Small peptides, by their nature, can be rapidly broken down by the body, which may limit their therapeutic window. The research team is actively exploring strategies to enhance the stability and longevity of BRP, with the goal of enabling a more practical and convenient dosing schedule for potential human use.
"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."
This sentiment is echoed by the broader scientific and medical communities, who are keenly anticipating the results of future human trials. The successful development of BRP could represent a significant advancement in obesity pharmacotherapy, offering a much-needed alternative with the potential for improved tolerability and a more targeted mechanism of action.
The research was a collaborative effort, with contributions from researchers at the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Funding for this extensive project was provided by 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 related to BRP peptides for metabolic disorders. Dr. Svensson is also a co-founder of Merrifield Therapeutics, a company established to advance the development of BRP.
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