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, published in the prestigious journal Nature on March 5, heralds a potential new era in the fight against obesity, offering a more targeted and potentially better-tolerated approach to weight management.
The molecule, designated BRP (BRINP2-related-peptide), operates through a distinct yet related metabolic pathway, activating a separate set of neurons in the brain. This crucial difference from semaglutide could offer a more precise tool for regulating appetite and body weight, minimizing the widespread effects that can lead to undesirable side effects.
A More Targeted Approach to Appetite Control
Assistant Professor of Pathology at Stanford Medicine, Katrin Svensson, PhD, explained the significance of BRP’s unique mechanism. "The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas, and other tissues," 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 nestled deep within the brain, plays a pivotal role in orchestrating a multitude of bodily functions, including hunger, satiety, body temperature regulation, hormone activity, and overall energy expenditure. By focusing its action primarily on this control center, BRP may offer the ability to influence appetite with fewer off-target effects throughout the body, a significant advantage over current treatments.
Recognizing the profound potential of this discovery, Dr. Svensson has co-founded a company poised to initiate clinical trials of BRP in humans in the near future. This transition from laboratory findings to human testing marks a critical milestone, bringing the promise of this new molecule closer to therapeutic reality. Dr. Svensson is the senior author of the research, with senior research scientist Laetitia Coassolo, PhD, serving as the lead author of the study.
Artificial Intelligence: The Key to Unlocking Hidden Peptides
The identification of BRP was heavily reliant on the sophisticated capabilities of artificial intelligence (AI). This advanced technology enabled researchers to efficiently navigate the complex landscape of proteins, specifically focusing on a class known as prohormones.
Prohormones are essentially inactive precursor molecules that require enzymatic cleavage to become biologically active peptides. These peptides then function as signaling molecules, transmitting crucial messages that influence a wide array of physiological processes, including metabolism, appetite regulation, and other intricate functions within the brain and the broader organism. The challenge lies in the fact that a single prohormone can be processed in multiple ways, yielding a multitude of peptides. Distinguishing the truly impactful peptide hormones from the vast number of incidental fragments generated during normal protein metabolism is a formidable task. Traditional laboratory methods, while capable of isolating and identifying peptides, can generate overwhelming quantities of data, necessitating the manual sifting through hundreds of thousands of molecules to pinpoint those with significant biological effects.
Searching for New Metabolic Signals with Precision
The Stanford team’s investigation centered on an enzyme named prohormone convertase 1/3 (PC1/3). This enzyme is known to cleave prohormones at specific amino acid sequences, and has previously been implicated in human obesity. By understanding the enzymatic activity of PC1/3, researchers hypothesized that it might be responsible for producing other peptides with a role in energy balance and appetite regulation.
Among the known peptides produced by PC1/3 is glucagon-like peptide 1 (GLP-1), a hormone that plays a significant role in regulating hunger and blood sugar levels. Semaglutide, the active ingredient in Ozempic and Wegovy, functions by mimicking the effects of GLP-1. The researchers reasoned that PC1/3 could be a source of novel peptides with similar or even enhanced metabolic signaling capabilities.
The Power of "Peptide Predictor": An AI-Driven Discovery Engine
To overcome the limitations of traditional methods, the researchers developed an innovative computer algorithm named "Peptide Predictor." This AI-powered tool revolutionized the search process. Instead of manually extracting and analyzing proteins and peptides from tissues using techniques like mass spectrometry, which can be labor-intensive and data-intensive, Peptide Predictor offered a more streamlined and predictive approach.
The algorithm systematically analyzed all 20,000 human protein-coding genes, searching for the characteristic sequences targeted by prohormone convertases. The research scope 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 intelligent filtering process dramatically reduced the number of candidate prohormones from thousands to a more manageable 373, a crucial step in making the investigation feasible.
"The algorithm was absolutely key to our findings," Dr. Svensson emphasized, underscoring the indispensable role of AI in their breakthrough.
Peptide Predictor further estimated that PC1/3 could potentially generate 2,683 distinct peptides from these 373 prohormones. Drs. Coassolo and Svensson then narrowed their focus to peptides that exhibited the highest probability of influencing brain function. They selected 100 peptides, including the well-known GLP-1, for experimental testing.
A Tiny Peptide with an Outsized Effect: The Discovery of BRP
The selected peptides were then tested for their ability to stimulate neuron-like cells cultured in the laboratory. As anticipated, GLP-1 demonstrated significant activity, increasing neuronal activity by threefold compared to untreated control cells. However, one particular peptide, BRP, a remarkably small molecule composed of just 12 amino acids, elicited an even more potent response, increasing neuronal activity by a tenfold margin. This magnitude of effect from such a minuscule peptide was unprecedented and immediately highlighted BRP as a molecule of significant interest.
The researchers named this potent peptide BRP, derived from its parent prohormone, BPM/retinoic acid inducible neural specific 2 (BRINP2). Amino acids are the fundamental building blocks of proteins and peptides. The extremely small size of BRP, relative to typical full-length proteins, belied its profound impact on neuronal signaling in the initial cell assays.
Pre-Clinical Efficacy: Reduced Food Intake and Fat Loss in Animal Models
Following the promising in vitro results, the research team advanced to pre-clinical studies using both lean mice and minipigs. Minipigs were chosen for their physiological similarities to humans in terms of metabolism and eating patterns, offering a more robust model than mice alone.
An intramuscular injection of BRP administered shortly before feeding resulted in a remarkable reduction in food intake, with intake falling by up to 50% within the hour following administration in both species. This immediate and significant suppression of appetite demonstrated BRP’s potent effect on satiety.
The study also included a 14-day trial with obese mice, where daily BRP injections were administered. On average, the treated obese mice experienced a weight loss of 3 grams, with the vast majority of this reduction attributed to a decrease in body fat. In stark contrast, the control group of obese mice gained approximately 3 grams over the same period, highlighting BRP’s efficacy in promoting fat loss.
Beyond weight reduction, the treated mice also exhibited improved glucose and insulin tolerance. These metabolic markers are critical indicators of how effectively the body manages blood sugar and responds to insulin, a key hormone for glucose uptake by cells. Enhanced glucose and insulin tolerance suggest that BRP may contribute to a healthier metabolic profile.
Addressing the Side Effect Conundrum: Promising Absence of Common Adverse Reactions
A critical aspect of the BRP research was the investigation into potential side effects. Behavioral testing revealed no significant differences between BRP-treated and untreated animals concerning movement, water consumption, anxiety-like behaviors, or fecal production.
The lack of impact on fecal production is particularly noteworthy, given that semaglutide is known to slow digestive transit and can lead to constipation in some individuals. Furthermore, the researchers did not observe any behaviors indicative of nausea, a common gastrointestinal side effect associated with GLP-1 receptor agonists. Crucially, the studies also did not detect any substantial muscle loss, a concern that has been associated with rapid weight loss achieved through some existing pharmacotherapies.
Additional physiological measurements confirmed that BRP operates through distinct metabolic and neuronal pathways compared to those activated by GLP-1 or semaglutide. This divergence in mechanism further supports the hypothesis that BRP may achieve its appetite-suppressing effects through a more localized and potentially safer biological route, although these findings are currently confined to animal models.
Navigating the Path to Human Trials: Future Directions and Challenges
As the research team prepares for human clinical trials, several key questions remain to be addressed. A primary objective is to identify the specific cell-surface receptors to which BRP binds. Understanding this interaction is paramount to fully elucidating how BRP modulates appetite and metabolism at a molecular level. Receptors act as the docking stations for signaling molecules, and their identification will provide crucial insights into BRP’s mechanism of action.
Furthermore, the researchers aim to meticulously map the complete cascade of events that occur subsequent to BRP binding to its target receptor. This detailed understanding will be essential for optimizing therapeutic strategies and predicting potential interactions.
Another significant challenge is the duration of BRP’s action. Small peptides are often rapidly metabolized and cleared from the body, which can limit their therapeutic window. The research team is actively exploring methods to enhance BRP’s stability and prolong its effects, aiming to facilitate a more practical dosing regimen 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 statement encapsulates the immense hope and scientific rigor driving the ongoing research.
The collaborative effort involved researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia, underscoring the interdisciplinary nature of this scientific endeavor. Funding for this groundbreaking research was provided by a consortium of esteemed 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, signifying their foundational contribution to this field. Additionally, Dr. Svensson is a co-founder of Merrifield Therapeutics, a company dedicated to advancing novel therapeutic solutions. The successful translation of BRP from a laboratory discovery to a potential human therapy could represent a significant advancement in addressing the global obesity epidemic, offering a new and potentially more tolerable option for millions worldwide.
