LEAP-2: The Body's Natural Ghrelin Blocker Emerges as a Promising Anti-Obesity Target | Research

The takeaway

LEAP-2, originally known as an antimicrobial peptide, is now recognized as the body's endogenous ghrelin receptor antagonist and inverse agonist, with circulating levels that inversely track ghrelin and correlate with energy status — making it a promising obesity therapeutic target.

Nature's appetite off-switch
LEAP-2 is the endogenous counterbalance to ghrelin — rising after meals to suppress hunger. Enhancing this natural system could provide physiological obesity treatment

What the researchers found

LEAP-2 acts as both competitive ghrelin antagonist and inverse agonist of constitutive GHS-R1a activity. LEAP-2 increases with feeding/obesity, decreases with fasting/weight loss — inverse to ghrelin. LEAP-2/ghrelin molar ratio fluctuates with energy status and modulates food intake.

Why it matters

The body already has a natural hunger suppressor that counters ghrelin. Understanding and enhancing LEAP-2 signaling could provide a physiological, targeted approach to obesity treatment — working with the body's own appetite regulation rather than against it.

The numbers in context

LEAP-2: competitive antagonist + inverse agonist of GHS-R1a; increases with feeding/obesity; decreases with fasting/weight loss

How the study worked

Narrative review of LEAP-2 biology, GHS-R1a pharmacology, circulating LEAP-2/ghrelin dynamics, and metabolic effects. Discussion of LEAP-2 as therapeutic target for obesity.

Who was studied

N/A (review of preclinical and human observational data)

What this study cannot tell us

Review article. LEAP-2 therapeutic applications are conceptual — no clinical trials yet. LEAP-2's effects on metabolic parameters beyond appetite need further study. The optimal LEAP-2/ghrelin ratio for weight management is unknown.

How to read the evidence

Not applicable (narrative review). Based on emerging basic science and preclinical evidence for LEAP-2's metabolic roles.

When this study was published

Published 2021. LEAP-2 research has accelerated with growing interest from pharmaceutical companies.

The bigger picture

LEAP-2 discovery transforms our understanding of appetite regulation from a single-hormone (ghrelin) model to a dual-hormone balance (ghrelin vs LEAP-2). This yin-yang system provides multiple intervention points for obesity therapy — boosting LEAP-2, blocking ghrelin, or both.

Questions still open

Could LEAP-2 analogues be developed as anti-obesity drugs?
Would LEAP-2 therapy complement GLP-1 drugs for additive weight loss?
Does low LEAP-2 contribute to weight regain after dieting?

Common questions

What is LEAP-2?

LEAP-2 (liver-expressed antimicrobial peptide 2) is a peptide produced by the liver that naturally blocks the ghrelin (hunger) receptor. It was originally thought to be just an immune peptide, but is now recognized as a key appetite regulator that rises after eating and falls during fasting.

Could boosting LEAP-2 help with weight loss?

Theoretically, yes. Since LEAP-2 naturally suppresses appetite by blocking ghrelin, enhancing its levels could reduce hunger. This is an early research concept — no LEAP-2 drugs are available yet, but it represents a promising target alongside GLP-1 drugs for obesity.

Read the original research

LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity.

Frontiers in endocrinology, 12, 717544

View on PubMed ↗Publisher’s paper ↗

Citation

Lu, Xuehan; Huang, Lili; Huang, Zhengxiang; Feng, Dandan; Clark, Richard J; Chen, Chen. (2021). LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity.. Frontiers in endocrinology, 12, 717544. https://doi.org/10.3389/fendo.2021.717544