Researchers at Stanford Medicine have pinpointed a natural molecule that replicates certain weight-loss outcomes of semaglutide, commonly known as Ozempic. Tests on animals showed it curbed hunger and decreased body weight, while sidestepping typical issues like nausea, constipation, and muscle reduction.
Named BRP, this molecule operates via a separate yet connected biological mechanism, stimulating specific brain neurons. This could enable a more focused method for managing hunger and metabolic functions.
According to Katrin Svensson, PhD, an assistant professor of pathology, semaglutide’s targets exist in the brain as well as the gut, pancreas, and other areas, leading to broad impacts such as delayed digestion and reduced blood sugar. BRP, however, seems to target only the hypothalamus, which oversees appetite and metabolism.
Svensson, who led the study published in Nature, has also established a company set to launch human trials soon. The primary author is Laetitia Coassolo, PhD, a senior research scientist.
The breakthrough stemmed from artificial intelligence analyzing prohormones, which are dormant molecules that can fragment into active peptides influencing metabolism.
Traditional approaches make spotting these useful peptides difficult amid numerous inactive pieces from protein degradation.
The team targeted prohormone convertase 1/3, an enzyme associated with obesity that produces GLP-1, which semaglutide imitates to control appetite and blood sugar.
They created an AI tool named Peptide Predictor to examine all 20,000 human genes coding for proteins, pinpointing potential peptide cuts.
Focusing on secreted proteins with multiple cleavage sites narrowed candidates to 373 prohormones.
Svensson noted the algorithm’s crucial role in the results.
From these, it forecasted 2,683 peptides. The scientists tested 100, including GLP-1, on cultured brain cells.
GLP-1 boosted neuron activity as anticipated, but a 12-amino-acid peptide showed a tenfold stronger effect.
Derived from BRINP2, it was dubbed BRP.
In trials with lean mice and minipigs, which resemble human metabolism better, BRP cut food intake sharply. One dose reduced eating by up to half within an hour.
Obese mice receiving daily doses over two weeks lost about 3 grams on average, mostly fat, while controls gained that amount. Treated subjects also had better glucose and insulin responses.
No alterations occurred in activity levels, hydration, anxiety, or gut function. Further checks revealed BRP uses distinct pathways from GLP-1 or semaglutide.
The team is now studying BRP’s receptors and bodily mechanisms, plus ways to prolong its duration for easier human application.
Svensson highlighted the long-standing challenge of obesity treatments, with semaglutide setting a high bar for appetite and weight control. They anticipate assessing its safety and efficacy in people.
The project included experts from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Support came from the National Institutes of Health via grants R01DK125260 and P30DK.
