Stanford Medicine researchers have discovered a naturally occurring molecule that can suppress appetite and promote weight loss, emulating the effects of semaglutide, the active component in Ozempic. In animal experiments, the molecule also avoided several adverse effects associated with the medication, such as nausea, constipation, and notable muscle loss.
The compound, designated BRP, operates via a distinct yet related metabolic route that engages a separate set of brain neurons. This specificity could enable more precise regulation of appetite and body weight.
A More Targeted Approach to Appetite Control
“The receptors that semaglutide engages are present not only in the brain but also in the gut, pancreas, and other tissues,” explained Katrin Svensson, PhD, assistant professor of pathology. “Consequently, Ozempic produces systemic effects such as slowed gastrointestinal transit and reduced blood glucose. Conversely, BRP appears to act selectively within the hypothalamus, the brain region that governs appetite and metabolic processes.”
The hypothalamus, a compact region deep within the brain, regulates hunger, body temperature, hormonal activity, and energy utilization. As BRP primarily targets this area, it may modulate appetite while sparing many peripheral effects.
Svensson has established a company that intends to initiate human clinical trials of the molecule shortly.
Svensson serves as the senior author of the study, published on March 5 in Nature. Laetitia Coassolo, PhD, senior research scientist, is the lead author.
Artificial Intelligence Reveals Hidden Peptides
The discovery relied heavily on artificial intelligence, enabling the researchers to scan proteins within the prohormone family.
Prohormones are inactive precursors that require enzymatic processing to become active peptides. Certain peptides function as hormones, transmitting signals that regulate metabolism, appetite, and other intricate physiological processes throughout the brain and body.
Searching for New Metabolic Signals
The investigators focused on an enzyme known as prohormone convertase 1/3, which cleaves prohormones at defined amino‑acid sequences and has been associated with obesity in humans.
One peptide generated by this mechanism is glucagon‑like peptide‑1 (GLP‑1), which modulates hunger and blood glucose; semaglutide mimics its actions in the body.
Peptide Predictor
Instead of manually extracting proteins and peptides for mass‑spectrometry analysis, the team developed a computational algorithm named Peptide Predictor.
The program screened all 20,000 human protein‑coding genes for sites typical of prohormone convertase cleavage. It subsequently filtered these to genes encoding secreted proteins with a minimum of four potential cleavage sites.
This approach narrowed the candidates to 373 prohormones, yielding a manageable dataset for further investigation.
“The algorithm was absolutely key to our findings,” Svensson said.
Peptide Predictor projected that prohormone convertase 1/3 could generate 2,683 distinct peptides from those 373 proteins. Coassolo and Svensson then prioritized sequences most likely to influence brain function.
They selected 100 peptides, including GLP‑1, and tested whether they could stimulate neuron‑like cells grown in the laboratory.
A Tiny Peptide With an Outsized Effect
As anticipated, GLP‑1 robustly activated the neuronal cells, elevating their activity to threefold that of untreated controls.
A considerably smaller peptide elicited an even greater response, boosting neuronal activity tenfold relative to controls, despite comprising only 12 amino acids.
The researchers named the peptide BRP after its parent prohormone, BPM/retinoic acid‑inducible neural‑specific protein 2 (BRINP2), commonly referred to as BRINP2‑related peptide.
Amino acids serve as the fundamental building blocks of proteins and peptides. Although a molecule consisting of only 12 amino acids is diminutive compared with typical full‑length proteins, BRP generated the most pronounced response in the initial cellular assays.
Food Intake Fell by Up to 50%
The investigators subsequently administered BRP to lean mice and minipigs — species whose metabolic and feeding behaviors more closely resemble those of humans than standard mice.
An intramuscular injection administered prior to feeding reduced subsequent food intake by up to 50% in both species over the ensuing hour.
The team also delivered daily BRP injections to obese mice for 14 days; on average, treated animals lost 3 g, primarily from fat mass, whereas control mice gained approximately 3 g during the same interval.
Treated mice also exhibited enhanced glucose tolerance and insulin sensitivity, indicating more efficient regulation of blood glucose and improved insulin‑mediated glucose uptake.
No Clear Signs of Common Side Effects
Behavioral assessments revealed no significant differences between treated and untreated animals regarding locomotion, water intake, anxiety‑like behavior, or fecal output.
The lack of alteration in fecal output was particularly noteworthy, given that semaglutide often slows gastrointestinal transit and induces constipation. Moreover, the researchers observed no nausea‑related responses or substantial muscle loss, common adverse effects of certain weight‑loss therapeutics.
Additional measurements of brain activity and physiological function demonstrated that BRP engages metabolic and neuronal pathways distinct from those modulated by GLP‑1 or semaglutide.
Questions Before Human Testing
The investigators are now seeking to identify the cell‑surface receptors that bind BRP. Receptors are molecular receptors that detect signals from hormones, drugs, and other chemical messengers; pinpointing the specific receptor for BRP will clarify precisely how the peptide modulates appetite and metabolism.
They also aim to map the complete cascade of events that follow BRP binding to its target.
A further challenge is the short duration of action; small peptides are rapidly degraded, limiting their therapeutic window. The researchers are exploring strategies to extend BRP’s stability, potentially enabling more practical dosing regimens in humans.
“The scarcity of effective anti‑obesity medications in humans has been a decades‑long challenge,” Svensson remarked. “We are eager to determine whether the peptide proves safe and effective in human trials.”
Researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia contributed to the work.
The study was funded 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.
Svensson and Coassolo are inventors on patents regarding BRP peptides for metabolic disorders. Svensson is a co-founder of Merrifield Therapeutics.