Rethinking Peptide Hormones in Obesity Treatment

By Prof. Nelly Pitteloud

A groundbreaking study published in Nature (May 2025) has unveiled a novel anti-obesity peptide that operates entirely outside of traditional weight-regulating pathways. The research, led by scientists at Stanford University and Merrifield Therapeutics, introduces a powerful new direction in metabolic science: using computational prediction of prohormone cleavage to discover hidden bioactive peptides—with real therapeutic promise.

Uncovering a New Hormone: The BRP Peptide

Peptide hormones like GLP-1 and leptin have long been key targets for obesity drugs. But what if the body contains many more natural hormones we've simply never identified?

That’s exactly what this study set out to investigate. By using a computational pipeline to map over 2,600 previously uncharacterized peptide fragments generated by enzymes like PCSK1/3 (a known prohormone convertase), the team predicted which of these fragments might function as metabolic regulators. This approach led to the discovery of a previously unknown 12-amino-acid peptide, now named BRP (BRINP2-related peptide).

BRP: A New Kind of Anti-Obesity Agent

When BRP was pharmacologically administered to mice and pigs, the effects were remarkable:

• Significantly reduced food intake

• Strong anti-obesity effects, even in diet-induced obese animals

• No signs of nausea or aversion, a common problem with current therapies like GLP-1 agonists

Unlike GLP-1, BRP acts independently of known satiety pathways including leptin, melanocortin 4 receptor (MC4R), and the GLP-1 receptor. Instead, it activates neuronal FOS, a marker of brain activity linked to feeding control, suggesting it may operate through a completely new mechanism.

A New Drug Discovery Paradigm

What makes this discovery particularly exciting is the method itself.

Rather than screening thousands of synthetic compounds or genetically modifying mice, researchers used computational prediction of enzymatic cleavage patterns to mine the human proteome for natural peptide fragments with bioactive potential.

This not only yielded BRP but opens the door to hundreds of other hidden peptides that could regulate metabolism, inflammation, or even cognition.

From Bench to Therapy

Although BRP is not yet in clinical trials, its safety profile in animal models and lack of nausea-inducing side effects make it an exceptionally promising candidate for obesity treatment.

In a time when GLP-1-based drugs dominate the market, BRP represents the first major non-incretin peptide with comparable efficacy. It could eventually serve as a standalone therapy or as a synergistic addition to existing treatments.

Why It Matters

Obesity is a multifactorial disease with few long-term, tolerable treatment options. This study demonstrates:

• That our bodies may contain undiscovered hormones with therapeutic potential.

• That computational biology can dramatically accelerate peptide drug discovery.

• That non-incretin, non-leptin pathways are viable for weight control—a shift that could benefit patients who don’t respond to current drugs.

As researchers continue to probe the hidden corners of the human proteome, discoveries like BRP could spark an entire new class of hormone-based therapies—tailored not just to suppress appetite, but to do so safely, sustainably, and with fewer side effects.

Original study: “Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide,” was published in Nature on May 2025 (DOI: 10.1038/s41586-025-08683-y).