A Groundbreaking Discovery in the Fight Against Obesity

Stanford Medicine researchers have made a groundbreaking discovery in the fight against obesity, identifying a naturally occurring molecule that may suppress appetite and reduce body weight in a way that resembles semaglutide, the active ingredient in Ozempic. The molecule, known as BRP, works through a different but related metabolic pathway and activates a separate group of neurons in the brain, which could make it a more precise tool for controlling appetite and body weight.

According to assistant professor of pathology Katrin Svensson, PhD, the receptors targeted by semaglutide are found in the brain but also in the gut, pancreas, and other tissues, resulting in 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 discovery depended heavily on artificial intelligence, which allowed the researchers to search through proteins belonging to a group known as prohormones. Prohormones are inactive precursor molecules that do not perform their final biological function until enzymes cut them into smaller fragments called peptides. Some of these peptides then act as hormones, carrying signals that influence metabolism, appetite, and other complex processes in the brain and throughout the body.

The researchers created a computer algorithm called Peptide Predictor, which searched all 20,000 human protein-coding genes for the types of sites where prohormone convertases typically cut proteins. The algorithm narrowed the search to genes that produce proteins secreted outside the cell, a common feature of hormones, and that contained at least four possible cleavage sites. This process reduced the field to 373 prohormones, giving the team a much more manageable group to investigate.

The Peptide Predictor estimated that prohormone convertase 1/3 could produce 2,683 distinct peptides from those 373 proteins. The researchers then focused on sequences that seemed most likely to affect the brain, selecting 100 peptides, including GLP-1, and testing whether they could stimulate neuron-like cells grown in the laboratory. As expected, GLP-1 strongly activated the neuronal cells, increasing their activity to three times the level seen in untreated control cells.

One much smaller peptide produced an even more dramatic response. Made from only 12 amino acids, it increased neuronal activity tenfold compared with controls. The researchers named the peptide BRP after its parent prohormone, BPM/retinoic acid inducible neural specific 2, or BRINP2 (BRINP2-related-peptide). Amino acids are the basic building blocks of proteins and peptides, and a molecule containing only 12 of them is extremely small compared with most full-sized proteins.

The researchers next tested BRP in lean mice and minipigs, which more closely mirror human metabolism and eating patterns than mice do. An intramuscular injection given before feeding reduced food intake during the following hour by as much as 50% in both species. The team also gave daily BRP injections to obese mice for 14 days, resulting in an average weight loss of 3 grams, with nearly all of the reduction coming from body fat.

The treated mice also showed improved glucose and insulin tolerance, reflecting how effectively the body regulates blood sugar and responds to insulin, the hormone that helps move glucose from the bloodstream into cells. Behavioral testing found no meaningful differences between treated and untreated animals in movement, water consumption, anxiety-like behavior, or fecal production.

The absence of changes in fecal production was especially notable because semaglutide can slow digestion and cause constipation. The researchers also did not observe the nausea-related responses or major muscle loss associated with some existing weight loss treatments. Additional measurements of brain activity and body function showed that BRP acts through metabolic and neuronal pathways that differ from those activated by GLP-1 or semaglutide.

The researchers are now working to identify the cell-surface receptors that attach to BRP. Receptors are molecular structures that receive signals from hormones, drugs, and other chemical messengers. Determining which receptor BRP uses will help scientists understand exactly how the peptide changes appetite and metabolism.