Stanford scientists identify natural molecule that suppresses appetite in animals

BRP works differently from semaglutide, the active ingredient in Ozempic. Instead of acting on several organs, it appears to act selectively on the hypothalamus, the brain region that controls hunger and metabolism.

"The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues," said Katrin Svensson, PhD, 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."

Semaglutide works by imitating GLP-1, a hormone that regulates blood sugar and signals that influence hunger. Because GLP-1 receptors are distributed throughout the body, activating them can produce effects beyond appetite control. Substantial muscle loss can accompany some weight-reduction treatments. BRP activates different populations of brain cells, which the researchers think could allow more precise appetite control with fewer unwanted effects.

The molecule was found using an AI algorithm called Peptide Predictor, which scanned the roughly 20,000 genes that encode human proteins for likely cutting sites of prohormone convertase 1/3, an enzyme previously linked to obesity. The approach narrowed the possibilities to 373 prohormones and an estimated 2,683 distinct peptides. The team tested 100 of them on nerve cells in the laboratory. BRP, a peptide of just 12 amino acids named after the BRINP2 protein it comes from, increased neuronal activity tenfold compared with untreated control cells, while GLP-1 increased it threefold. "The algorithm was absolutely key to our findings," Svensson said.

In lean mice and minipigs, an injection of BRP before feeding cut food intake by up to 50 percent in the following hour. Obese mice given daily injections for 14 days lost an average of 3 grams, while untreated controls gained about 3 grams. Nearly all the weight lost came from body fat rather than muscle, and the treated animals also showed improvements in glucose and insulin tolerance.

The researchers monitored the animals for signs of side effects and found no significant differences in movement, water consumption, anxiety-related behavior or fecal output, the last of which is relevant because constipation is a known side effect of Ozempic. Whether BRP would prevent nausea in people cannot be established from animal experiments, they noted.

Further work is needed to identify the cell surface receptors BRP activates and investigate ways to extend the peptide’s activity, as peptides can be broken down relatively quickly. Svensson has cofounded a company, Merrifield Therapeutics, to advance BRP toward human clinical trials.

"The lack of effective drugs to treat obesity in humans has been a problem for decades," Svensson said. "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."