Stanford Researchers Identify Potential Appetite Suppressant with Fewer Side Effects than Semaglutide

A team of Stanford Medicine researchers has discovered a naturally occurring molecule, referred to as BRP, which may effectively suppress appetite and facilitate weight loss with fewer side effects than the widely used diabetes drug Ozempic, known for its active ingredient semaglutide.

Stanford Medicine researchers have identified a naturally occurring molecule that may suppress appetite and reduce body weight in a way that resembles semaglutide, the active ingredient in Ozempic. In animal studies, the molecule, known as BRP, demonstrated potential in avoiding several common side effects associated with semaglutide, including nausea, constipation, and significant muscle loss.

Published in the journal Nature on March 5, the study outlines how BRP operates through a different metabolic pathway and activates distinct neurons in the brain, possibly making it a more targeted option for appetite control. Assistant Professor of Pathology Katrin Svensson, PhD, who is also the senior author of the research, emphasized the precision of BRP: “The receptors targeted by semaglutide are found in the brain but also in the gut, pancreas and other tissues. 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.”

A Deeper Understanding of Appetite Regulation

The hypothalamus, a small yet crucial area deep within the brain, plays a significant role in regulating hunger, body temperature, hormone activity, and energy expenditure. The potential of BRP to primarily influence appetite within this region may result in fewer systemic side effects.

In addition to her academic contributions, Dr. Svensson has co-founded a company that plans to initiate clinical trials of BRP in humans in the near future.

The Role of Artificial Intelligence in Discovery

The discovery of BRP relied significantly on artificial intelligence, which enabled the researchers to sift through proteins belonging to a group known as prohormones. Prohormones are inactive molecules that require enzymatic processing into smaller fragments, called peptides, to fulfill their biological functions. Identifying biologically active peptides is challenging due to the vast number of ordinary fragments generated during normal protein processing.

The research team focused on an enzyme called prohormone convertase 1/3, which has been linked to obesity in humans. This enzyme can produce glucagon-like peptide 1 (GLP-1), which is known to regulate hunger and blood sugar levels, and serves as a model for how semaglutide operates in the body. The researchers hypothesized that other peptides produced by the same enzyme might also influence energy balance and appetite.

To uncover these peptides, the researchers developed an algorithm called Peptide Predictor. This program scanned all 20,000 human protein-coding genes for sites where prohormone convertases typically cleave proteins. By narrowing their search to genes associated with extracellular secretion and containing multiple cleavage sites, the team reduced the candidates to 373 prohormones for further investigation.

Dr. Svensson noted, “The algorithm was absolutely key to our findings.” The Peptide Predictor estimated that the prohormone convertase 1/3 could generate 2,683 distinct peptides from the selected prohormones. The researchers subsequently tested 100 peptides, including GLP-1, to see if they could stimulate neuron-like cells in laboratory conditions.

BRP’s Impact on Food Intake

The research revealed that GLP-1 significantly activated neuronal cells, increasing their activity threefold compared to untreated controls. However, a smaller peptide derived from only 12 amino acids, named BRP after its parent prohormone BPM/retinoic acid-inducible neural-specific 2, produced an even more striking result, boosting neuronal activity tenfold.

The team then progressed to testing BRP in lean mice and minipigs, which provide a closer approximation to human metabolism. An intramuscular injection of BRP prior to feeding resulted in a reduction of food intake by as much as 50% in both species. Additionally, daily BRP injections administered to obese mice over 14 days resulted in an average weight loss of 3 grams, primarily from body fat, while control mice gained weight during the same period. The treated mice also exhibited improved glucose and insulin tolerance, indicating enhanced metabolic regulation.

Promising Results with Minimal Side Effects

Behavioral assessments indicated no significant differences between treated and untreated animals in terms of movement, water consumption, anxiety-like behavior, or fecal production, a notable finding given that semaglutide can induce constipation. The absence of nausea or major muscle loss typically seen with other weight-loss medications further suggests BRP’s potential as a safer alternative.

As the research team continues their investigations, they aim to identify the cell-surface receptors that interact with BRP. Understanding these receptors will be critical in elucidating how BRP influences appetite and metabolism. Another area of focus is enhancing the duration of BRP’s effects, as small peptides are often rapidly degraded in the body, limiting their therapeutic potential.

Dr. Svensson remarked on the ongoing challenge of developing effective obesity treatments: “The lack of effective drugs to treat obesity in humans has been a problem for decades. 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.”

Collaboration on this study also involved researchers from the University of California, Berkeley; the University of Minnesota; and the University of British Columbia. Funding came from various sources including the National Institutes of Health and the Stanford Bio-X initiative, among others. Notably, Svensson and lead author Laetitia Coassolo, PhD, hold patents related to BRP peptides for metabolic disorders.