LEAP2 curbed appetite in men with obesity
In a small randomized crossover study, an intravenous infusion of LEAP2, an endogenous ghrelin receptor antagonist, reduced ad libitum food intake and lowered post-meal glucose in men with obesity.
If you’ve been anywhere near the weight loss conversation lately, you’ve felt how dominant glucagon-like peptide‑1 (GLP‑1) drugs have become.
But appetite biology has other levers. One of the loudest is ghrelin, a hormone that rises before meals and helps generate that sharpened, insistent feeling of hunger.
A paper published in Diabetes tested a different idea: instead of adding another “you’re full” signal, what if you turn down the hunger signal.
The molecule is liver-expressed antimicrobial peptide 2 (LEAP2), a naturally occurring peptide that acts as a ghrelin receptor antagonist and inverse agonist. In a small, tightly controlled human study, researchers report that an intravenous LEAP2 infusion reduced how much men with obesity ate at an ad libitum meal and lowered post-meal glucose excursions.
The study: LEAP2 Reduces Ad Libitum Food Intake and Attenuates Postprandial Glucose Excursions in Men With Obesity.
What they did
The design here is the kind you want early in human physiology work.
Twenty men with obesity completed two experimental visits in a randomized, double-blind, placebo-controlled crossover setup. On one visit they received an approximately five-hour intravenous infusion of LEAP2, and on the other visit they received placebo.
During each visit, participants did a liquid mixed meal test followed by an ad libitum meal test, which is basically the pragmatic outcome: once you’ve controlled the setting, do people actually eat less when they’re allowed to eat freely.
The authors report that the LEAP2 infusion produced about a fivefold increase in measured plasma LEAP2 levels compared with placebo.
What changed
Two headline outcomes moved in the direction you’d expect if you’re successfully dialing down ghrelin signaling.
First, the LEAP2 infusion reduced ad libitum food intake by around 12% compared with placebo.
Second, it lowered postprandial plasma glucose levels, suggesting an acute metabolic effect beyond just “ate slightly less at one meal.”
This is not a claim about long-term weight loss. It is a short-window physiology result. But it is a real, randomized human datapoint in a population where appetite signaling is clinically relevant.
Why this matters
LEAP2 is interesting because it’s an example of why peptides can feel “magical” to outsiders.
A small molecule might have to hit multiple targets to create a similar appetite effect, with all the collateral risk that comes with broad binding. A peptide that fits a signaling system can sometimes act more like a very specific sentence addressed to one receptor.
At the same time, this study also shows the tradeoff: delivery and duration are the entire plot.
An intravenous infusion is a valid way to answer “does this biology work in humans,” but it is not, by itself, a practical therapy. The next chapters would need to show whether a LEAP2-like approach can be delivered in a patient-friendly way, for long enough to matter, with a safety profile that holds up.
(And even in the GLP‑1 world, real life can be complicated by counseling constraints, monitoring, and special populations. We’ve covered one example in GLP‑1 drugs, fertility, contraception, and pregnancy.)
What we know vs what we don’t
What we know:
In a small crossover study in men with obesity, an intravenous LEAP2 infusion increased circulating LEAP2 levels, reduced ad libitum food intake by about 12%, and lowered post-meal glucose excursions.
What we don’t know yet:
Whether these acute effects translate into durable weight loss or meaningful clinical outcomes.
Whether a LEAP2-based drug can be delivered conveniently (route, dosing frequency) while maintaining efficacy.
How this performs across broader populations, including women, older adults, and people with different metabolic phenotypes.
Further reading
- LEAP2 infusion study in men with obesity (2026, Diabetes): https://pubmed.ncbi.nlm.nih.gov/41911360/