Stanford Medicine researchers have unveiled the discovery of a naturally occurring molecular compound that exhibits significant promise in suppressing appetite and facilitating weight reduction, drawing parallels to the mechanism of semaglutide, the key ingredient in widely recognized medications like Ozempic. Crucially, initial investigations in animal models suggest this novel molecule may circumvent several of the gastrointestinal and metabolic disturbances commonly associated with existing pharmaceutical interventions, such as nausea, constipation, and a noticeable depletion of muscle mass.
The molecule, designated BRP (BRINP2-related-peptide), operates via a distinct yet interconnected metabolic pathway within the body. Its unique action involves the activation of a specific subset of neurons located in the brain, a differentiation that researchers believe could offer a more precisely targeted approach to modulating appetite and managing body weight. This specificity is a key distinguishing factor when compared to current treatments.
Explaining the rationale behind this targeted approach, Dr. Katrin Svensson, an assistant professor of pathology at Stanford Medicine and senior author of the study, elaborated on the differential distribution of receptor sites. "The receptors that semaglutide interacts with are not confined solely to the brain; they are also present in the digestive tract, the pancreas, and various other tissues," Dr. Svensson stated. "This widespread presence is the reason why Ozempic exerts a broad range of effects, including the deceleration of food transit through the digestive system and a reduction in blood sugar levels." In stark contrast, BRP appears to exert its primary influence within the hypothalamus, a brain region critically involved in the regulation of appetite and overall metabolism.
The hypothalamus, a compact yet vital area nestled deep within the brain, plays a pivotal role in orchestrating fundamental physiological processes, including the sensation of hunger, the maintenance of body temperature, the intricate regulation of hormone activity, and the efficient utilization of energy. The observed localization of BRP’s action predominantly within this region suggests a potential for influencing appetite signals without eliciting the extensive cascade of secondary effects seen with more broadly acting agents. Dr. Svensson has initiated the formation of a company with the express purpose of advancing this discovery towards human clinical trials in the immediate future.
The comprehensive research detailing this discovery was published on March 5th in the prestigious scientific journal Nature. Dr. Laetitia Coassolo, a senior research scientist at Stanford, served as the lead author of this groundbreaking study.
The identification of BRP was heavily reliant on the sophisticated capabilities of artificial intelligence, which empowered the research team to meticulously sift through vast quantities of data pertaining to proteins classified as prohormones. Prohormones are essentially inactive precursor molecules that require enzymatic cleavage to yield smaller, biologically active fragments known as peptides. These peptides then function as signaling molecules, or hormones, transmitting vital information that governs a multitude of complex bodily processes, including metabolism, appetite regulation, and other critical functions within the brain and across the entire organism.
A single prohormone can be processed through multiple enzymatic pathways, resulting in the generation of a diverse array of peptides. The challenge lies in discerning which of these peptides are truly biologically significant, as authentic peptide hormones are relatively scarce and can be easily overlooked amidst the multitude of ordinary fragments produced during normal protein turnover and degradation. Traditional laboratory methodologies for isolating and identifying peptides can be labor-intensive and generate immense datasets, often requiring researchers to meticulously examine hundreds of thousands of molecular entities to pinpoint those with meaningful physiological impact.
The research team strategically focused their investigation on an enzyme known as prohormone convertase 1/3. This specific enzyme is responsible for cleaving prohormones at particular amino acid sequences, and its dysfunction has been previously implicated in human obesity. It is this very enzyme that is known to process one of the peptides involved in appetite regulation: glucagon-like peptide 1 (GLP-1). GLP-1 plays a crucial role in managing hunger and blood glucose levels, and it is the biological mimicry of these effects that forms the basis of semaglutide’s therapeutic action. The Stanford researchers hypothesized that the same enzyme might also be responsible for producing other peptides with significant roles in energy balance and appetite control. This hypothesis led them to leverage artificial intelligence to uncover these hidden signals.
Rather than relying on conventional, labor-intensive methods of extracting proteins and peptides from biological tissues and then employing techniques like mass spectrometry to identify countless molecules, the researchers developed a sophisticated computational tool named Peptide Predictor. This innovative program systematically analyzed all 20,000 human protein-coding genes, searching for the specific types of sites where prohormone convertases are known to cleave proteins. The search was further refined to include only genes that produce proteins secreted outside the cell, a characteristic common to hormones, and that possessed a minimum of four potential cleavage sites. This rigorous filtering process successfully narrowed the field of potential candidates down to a more manageable 373 prohormones, significantly streamlining the subsequent investigation.
"The algorithm was absolutely instrumental to our findings," emphasized Dr. Svensson, underscoring the pivotal role of AI in the discovery process. Peptide Predictor further estimated that prohormone convertase 1/3 could generate as many as 2,683 distinct peptides from these 373 parent proteins. Dr. Coassolo and Dr. Svensson then strategically prioritized their investigation towards peptide sequences that demonstrated the highest likelihood of influencing neural activity in the brain. From this prioritized list, they selected 100 peptides, including GLP-1, and subjected them to experimental testing to ascertain their ability to stimulate neuron-like cells cultured in a laboratory setting.
As anticipated, GLP-1 demonstrated a potent ability to activate these neuronal cells, augmenting their activity to three times the baseline level observed in untreated control cultures. However, a significantly smaller peptide, comprising a mere 12 amino acids, elicited an even more pronounced response. This minuscule peptide, which the researchers subsequently named BRP, amplified neuronal activity by a remarkable tenfold increase compared to the control group. The designation BRP originates from its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2. Given that amino acids are the fundamental building blocks of proteins and peptides, a molecule composed of just 12 amino acids is exceptionally small, yet BRP exhibited the most robust stimulatory effect in these initial cellular assays.
Subsequent investigations transitioned to evaluating BRP’s efficacy in live animal models. The researchers administered BRP to both lean mice and minipigs, the latter chosen for their metabolic and dietary patterns that more closely approximate those of humans than mice. An intramuscular injection of BRP administered prior to feeding resulted in a substantial reduction in food intake, by as much as 50%, within the subsequent hour in both species. Over a 14-day period, obese mice receiving daily BRP injections experienced an average weight loss of 3 grams, with the majority of this reduction attributed to a decrease in body fat mass. In contrast, the control group of mice showed a weight gain of approximately 3 grams during the same timeframe. Furthermore, the BRP-treated mice displayed notable improvements in glucose tolerance and insulin sensitivity, indicating a more efficient regulation of blood sugar and a better cellular response to insulin.
Crucially, behavioral assessments revealed no significant disparities between the BRP-treated and untreated animals concerning parameters such as motor activity, water consumption, anxiety-like behaviors, or fecal output. The absence of any alteration in fecal production is particularly noteworthy, given that semaglutide is known to slow digestive processes and can lead to constipation. The researchers also reported no observations of nausea-related responses or substantial muscle wasting, side effects that have been associated with certain existing weight-loss therapies. Further analyses of brain activity and physiological functions indicated that BRP operates through distinct metabolic and neuronal pathways that diverge from those activated by GLP-1 or semaglutide, suggesting a potentially more selective mechanism of action for appetite reduction, although these findings are currently limited to preclinical observations.
Looking ahead, the research team is actively engaged in identifying the specific cell-surface receptors to which BRP binds. Understanding these receptor interactions is paramount for elucidating the precise mechanisms by which this peptide influences appetite and metabolism. Additionally, the researchers aim to meticulously map the complete sequence of molecular events that transpire subsequent to BRP binding to its target receptor. A significant challenge also lies in addressing the pharmacokinetic profile of small peptides, which are often rapidly metabolized in the body, potentially limiting the duration of their therapeutic effects. Consequently, efforts are underway to develop strategies for enhancing BRP’s stability and prolonging its action, with the ultimate goal of enabling a more practical dosing schedule for potential human application. "The persistent lack of effective therapeutic options for treating obesity in humans has been a significant challenge for decades," Dr. Svensson commented. "To date, no other compound we have investigated has demonstrated the same capacity as semaglutide to reduce appetite and body weight. We are exceptionally keen to ascertain its safety and efficacy in human subjects." Collaborative contributions to this research effort were made by scientists from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Funding for this study was provided by grants 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 hold patents related to BRP peptides for metabolic disorders, and Dr. Svensson is a co-founder of Merrifield Therapeutics.
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