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, published on March 5th in the prestigious journal Nature, marks a significant advancement in the ongoing quest for more effective and tolerable obesity treatments. The newly identified molecule, dubbed BRP (BRINP2-related-peptide), operates through a distinct metabolic pathway, potentially offering a more targeted approach to appetite control and body weight regulation. This breakthrough, heavily reliant on artificial intelligence, opens a promising new avenue for therapeutic interventions in a field grappling with a global obesity epidemic.
A Novel Mechanism for Appetite Regulation
Unlike semaglutide, which mimics the action of glucagon-like peptide 1 (GLP-1) and affects receptors found throughout the body, BRP appears to exert its effects primarily within the hypothalamus. This critical brain region is the body’s central command center for regulating hunger, satiety, metabolism, and energy expenditure.
"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," explained Dr. Katrin Svensson, 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."
This targeted action is crucial. By focusing its activity within the hypothalamus, BRP may influence appetite and reduce food intake without triggering the gastrointestinal distress and other systemic side effects commonly associated with drugs that act on a broader range of GLP-1 receptors. The hypothalamus, a small but vital area deep within the brain, orchestrates a complex array of physiological processes, including hunger cues and energy balance. A molecule that can precisely modulate its activity holds immense therapeutic potential.
The Power of Artificial Intelligence in Peptide Discovery
The identification of BRP was made possible by the innovative application of artificial intelligence. The research team leveraged AI to sift through a vast landscape of prohormones – inactive precursor molecules that are cleaved by enzymes into smaller, biologically active peptides. This process is akin to finding a specific needle in an immense haystack, as a single prohormone can yield numerous peptide fragments, only a select few of which possess significant biological activity.
"Traditional laboratory methods can isolate and identify peptides, but the process can produce enormous amounts of data. Researchers may need to sort through hundreds of thousands of molecules to find the few that have meaningful effects," Dr. Svensson noted.
The researchers focused on an enzyme known as prohormone convertase 1/3 (PC1/3), which plays a critical role in processing prohormones and has previously been linked to obesity in humans. Notably, GLP-1, the target of semaglutide, is one of the peptides produced by this enzyme. The Stanford team hypothesized that PC1/3 might also be responsible for generating other peptides that influence energy balance and appetite.
To test this hypothesis, they developed a sophisticated computer algorithm called "Peptide Predictor." This AI tool systematically scanned all 20,000 human protein-coding genes, identifying sites where PC1/3 typically cleaves proteins. The search was further refined to include genes producing proteins secreted outside the cell and containing at least four potential cleavage sites – characteristics common to hormones. This AI-driven approach dramatically narrowed the field of potential candidates from thousands to a manageable 373 prohormones.
"The algorithm was absolutely key to our findings," Dr. Svensson emphasized.
The Peptide Predictor further estimated that PC1/3 could generate 2,683 distinct peptides from these 373 prohormones. Dr. Svensson and lead author Dr. Laetitia Coassolo, a senior research scientist at Stanford Medicine, then prioritized sequences that showed the highest likelihood of impacting brain function. They selected 100 peptides, including GLP-1, for further investigation.
BRP: A Tiny Molecule with a Mighty Impact
Initial laboratory tests involved exposing neuron-like cells to these selected peptides. As anticipated, GLP-1 robustly activated the cells, tripling their activity. However, one much smaller peptide, BRP, produced an even more striking response. Composed of just 12 amino acids – a remarkably small size for a biologically active molecule – BRP amplified neuronal activity by a tenfold margin compared to control cells. This potent effect from such a diminutive peptide underscored its potential significance. The researchers named this molecule BRP after its parent prohormone, BPM/retinoic acid inducible neural specific 2 (BRINP2).
The promising results from cell cultures prompted the researchers to move to animal studies. They tested BRP in both lean mice and minipigs, the latter chosen for their metabolic and eating patterns that more closely resemble those of humans. A single intramuscular injection of BRP administered before feeding led to a remarkable reduction in food intake, as much as 50%, within the following hour in both species.
Further studies involved administering daily BRP injections to obese mice for a 14-day period. The treated animals experienced an average weight loss of 3 grams, with almost all of this reduction attributed to body fat. In stark contrast, the control group of mice gained approximately 3 grams during the same timeframe. Beyond weight loss, the BRP-treated obese mice also exhibited improved glucose and insulin tolerance, key indicators of metabolic health and efficient blood sugar regulation.
Addressing the Side Effects of Existing Treatments
A significant aspect of the BRP discovery is its apparent lack of the common side effects associated with semaglutide and other weight-loss medications. Behavioral testing in animals revealed no meaningful differences in movement, water consumption, anxiety, or fecal production between treated and untreated groups. The absence of changes in fecal production is particularly noteworthy, as semaglutide’s effect of slowing digestion can lead to constipation. The researchers also did not observe any signs of nausea-related responses or significant muscle loss, which have been concerns with some current weight-loss interventions.
These observations suggest that BRP’s distinct mechanism of action, operating through metabolic and neuronal pathways separate from those targeted by GLP-1 or semaglutide, may be responsible for its more favorable side effect profile. While these findings are currently limited to animal models, they provide a strong foundation for optimism regarding human safety and tolerability.
The Road Ahead: Clinical Trials and Future Developments
With these encouraging preclinical results, Dr. Svensson and her colleagues are now poised to advance BRP into human clinical trials. A company co-founded by Dr. Svensson plans to initiate these trials in the near future. The researchers are actively working to identify the specific cell-surface receptors that BRP binds to. Understanding this interaction is crucial for fully elucidating how the peptide influences appetite and metabolism at a molecular level.
Furthermore, the team aims to map the complete cascade of events that occur after BRP engages its target receptor. Another important area of investigation is the duration of BRP’s effects. Small peptides can sometimes be rapidly broken down by the body, limiting their therapeutic window. Researchers are exploring strategies to enhance BRP’s stability and longevity, aiming for a dosing schedule that is practical for human use.
"The lack of effective drugs to treat obesity in humans has been a problem for decades," Dr. Svensson stated. "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 global obesity crisis represents a significant public health challenge, with estimates from the World Health Organization indicating that over 1.9 billion adults worldwide were overweight in 2016, and of these, over 650 million were obese. The economic and healthcare burdens associated with obesity-related diseases, including type 2 diabetes, cardiovascular disease, and certain cancers, are immense. Semaglutide and similar GLP-1 receptor agonists have shown remarkable efficacy in promoting weight loss, but their widespread use is tempered by concerns about side effects and accessibility.
The discovery of BRP offers a potential paradigm shift. If its promising profile in animal studies translates to humans, it could provide a much-needed therapeutic option for individuals struggling with obesity, offering a path towards healthier weight management with fewer debilitating side effects. The scientific community will be keenly watching the progress of BRP through clinical trials, as it holds the promise of transforming the landscape of obesity treatment.
This groundbreaking research involved collaboration with scientists from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. The study was supported by substantial funding from the National Institutes of Health, 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, and Dr. Svensson is a co-founder of Merrifield Therapeutics, a company dedicated to developing novel therapeutics.
