Introduction
Discovery of the non-incretin peptide hormone
Mechanism of action
Comparative analysis with ozempic
Future research and potential applications
Conclusion
The World Health Organization (WHO) reports that more than 40% of adults worldwide are overweight or obese — a statistic that has nearly tripled since 1975.1,2 However, sustainable weight loss remains one of the greatest challenges in modern medicine.
The rising prevalence of obesity has provided impetus for the development of effective weight loss treatments. Furthermore, excess body weight is also linked to an increased risk of type 2 diabetes, cardiovascular disease, and other metabolic disorders, making obesity a significant public health concern.3
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Introduction
Dietary and herbal supplements, including taxifolin, green tea extract, chromium picolinate, ephedra, guarana, caffeine, and hydroxycitric acid, have been studied for weight loss due to their effects on metabolism, appetite suppression, and fat oxidation.2,4 However, their long-term safety remains unclear, with some linked to liver and kidney damage.4
Systematic reviews on herbal preparations like ephedra, green tea, Garcinia cambogia, and Bofutsushosan indicate mechanisms such as appetite suppression and thermogenesis.5 While some trials show modest weight loss, others highlight serious risks, such as ephedra’s cardiovascular effects, leading to its ban in multiple countries.5 Garcinia cambogia and green tea extract show inconsistent results, with safety concerns often poorly documented.5
Given these uncertainties, pharmacological interventions like GLP-1 receptor agonists, such as semaglutide (Ozempic), have gained attention for weight loss.6 Semaglutide mimics incretin hormones, enhancing insulin secretion, delaying gastric emptying, and suppressing appetite, leading to approximately 12% weight loss in clinical trials.6 However, it carries risks like nausea, vomiting, pancreatitis, and high costs, limiting accessibility.7
To address these issues, researchers are investigating naturally occurring peptides. Computational peptide discovery has led to BRINP2-related peptide (BRP), a non-incretin hormone identified through prohormone cleavage prediction.8
This article explores BRP’s discovery, mechanism, efficacy, and potential as a natural alternative to GLP-1 receptor agonists.
Discovery of the non-incretin peptide hormone
A recently published study by a team of scientists from Stanford University identified BRP using Peptide Predictor, a computational tool that the team developed to systematically map the proteolytic peptide fragments formed through cleavage by prohormone convertases.
This method allowed the researchers to screen over 2,600 previously uncharacterized peptides, ultimately leading to the identification of BRP. Unlike GLP-1 analogs, BRP does not interact with the GLP-1 receptor, making it mechanistically distinct from existing weight loss medications.8
Preclinical studies revealed that BRP administration significantly reduced food intake and promoted weight loss in mice and pigs. Importantly, these effects occurred independently of leptin, GLP-1, or melanocortin 4 receptor signaling, indicating a unique appetite-regulation mechanism.8
Additionally, BRP did not induce nausea or aversion in animal models, suggesting a potentially improved tolerability profile compared to Ozempic and other GLP-1-based therapies.
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Mechanism of action
BRP exerts its effects through central and peripheral pathways that modulate energy homeostasis. Unlike GLP-1 agonists, which primarily act by delaying gastric emptying and enhancing insulin secretion, BRP operates via the following mechanisms:
Hypothalamic activation: BRP triggers the expression of the FOS gene, a key marker of neuronal activation associated with appetite suppression, in the hypothalamus.8 This suggests that BRP directly influences brain circuits regulating hunger and satiety.
Increased lipid oxidation and energy expenditure: Unlike incretin-based therapies, which primarily affect insulin secretion and glucose metabolism, BRP enhances lipid oxidation, leading to increased fat burning and metabolic activity without causing glycemic instability.
Absence of gastrointestinal side effects: One of the most significant advantages of BRP over semaglutide in animal studies is its lack of nausea and aversion. The researchers believe that this improved tolerability may enhance long-term adherence among individuals seeking sustained weight loss.8
Adipose metabolism: Additionally, BRP has been observed to influence adipose tissue metabolism, increasing thermogenesis in brown adipose tissue.8 This suggests that BRP not only reduces food intake but also enhances energy expenditure, making it a dual-action weight loss agent.
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Comparative analysis with ozempic
While both BRP and semaglutide demonstrate potent weight loss effects, their mechanisms of action, efficacy, and tolerability differ significantly. Semaglutide is a GLP-1 receptor agonist that mimics incretin hormones to enhance insulin secretion, delay gastric emptying, and suppress appetite.6
In contrast, BRP operates through a non-incretin pathway, targeting the hypothalamus to regulate energy balance independently of GLP-1 receptor activation.8
In terms of appetite suppression, both agents are highly effective. Semaglutide activates the GLP-1 receptor to reduce hunger, while BRP suppresses appetite through direct hypothalamic activation. Preclinical studies have shown that BRP administration reduced food intake by up to 50% in mice within an hour.8
Semaglutide has been rigorously tested in human clinical trials, demonstrating an average placebo-corrected weight loss of approximately 12% over 68 weeks.7 Although BRP is still in the preclinical stage, it has shown significant fat loss in animal studies, suggesting strong potential for human application.8
Where the two agents differ markedly is in the risk of adverse reactions. Semaglutide is known to frequently cause gastrointestinal issues, including nausea, vomiting, and diarrhea, which can limit its tolerability for some patients.7
Furthermore, loss of muscle mass has also been associated with Ozempic use, with even popular media reporting drastic changes in appearance in Ozempic users. In contrast, BRP has not demonstrated any noticeable adverse effects in animal models, suggesting a potentially superior safety profile.8
However, while semaglutide improves insulin secretion and glycemic control, making it particularly beneficial for individuals with type 2 diabetes, BRP’s effects on glucose metabolism remain unclear and require further investigation.6,8
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Future research and potential applications
Although BRP presents a promising candidate for obesity treatment, additional research is needed to translate preclinical findings into clinical applications. Laetitia Coassolo, the lead researcher on the study that discovered BRP, and her team believe that future investigation on the efficacy, safety, and long-term impacts of BRP should consist of large-scale clinical trials to validate BRP’s safety and effectiveness across diverse populations.8
Evaluating BRP’s impact on metabolic markers, cardiovascular health, and sustained weight maintenance will be essential for regulatory approval and clinical adoption. Additionally, understanding the bioavailability, metabolic stability, and optimal dosing strategies for BRP will be crucial for its therapeutic success.
Furthermore, given its distinct mechanism of action, BRP could be explored as a complementary therapy alongside existing weight loss medications, such as GLP-1 receptor agonists.
Conclusions
The discovery of BRP through prohormone cleavage prediction represents a significant breakthrough in obesity research. By functioning independently of the incretin pathway, BRP offers a novel therapeutic approach with fewer side effects compared to GLP-1 agonists like Ozempic.
While further research is needed to validate its safety and efficacy in humans, BRP has the potential to emerge as a viable, naturally derived alternative for effective and well-tolerated weight management.
References
- World Health Organization. (2024, March 1). Obesity and overweight. Available at https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight [Accessed on 17 March, 2025]
- Hattori, Y., Nakaoku, Y., Ogata, S., Saito, S., Nishimura, K., & Ihara, M. (2025). Taxifolin as a Therapeutic Potential for Weight Loss: A Retrospective Longitudinal Study. Nutrients, 17(4), 706. https://doi.org/10.3390/nu17040706
- Cox C. E. (2017). Role of Physical Activity for Weight Loss and Weight Maintenance. Diabetes Spectrum : A Publication of the American Diabetes Association, 30(3), 157–160. https://doi.org/10.2337/ds17-0013
- Ng, J. Y., Ahmed, S., & Zhang, C. J. (2021). Dietary and herbal supplements for weight loss: assessing the quality of patient information online. Nutrition Journal, 20(1), 72. https://doi.org/10.1186/s12937-021-00729-x
- Teng, L., Lee, E. L., Zhang, L., & Barnes, J. (2020). Herbal preparations for weight loss in adults. The Cochrane Database of Systematic Reviews, 2020(4), CD013576. https://doi.org/10.1002/14651858.CD013576
- Knudsen, L. B., & Lau, J. (2019). The Discovery and Development of Liraglutide and Semaglutide. Frontiers in Endocrinology, 10, 155. https://doi.org/10.3389/fendo.2019.00155
- Gao, X., Hua, X., Wang, X., Xu, W., Zhang, Y., Shi, C., & Gu, M. (2022). Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: A systematic review and meta-analysis of randomized controlled trials. Frontiers in Pharmacology, 13, 935823. https://doi.org/10.3389/fphar.2022.935823
- Coassolo, L., B. Danneskiold-Samsøe, N., Nguyen, Q. et al. (2025). Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide. Nature. https://doi.org/10.1038/s41586-025-08683-y
Further Reading