The first LEAP2-knockout mice showed dramatically heightened ghrelin sensitivity, and females without LEAP-2 gained 15% more weight on a high-fat diet with 42% more liver fat, reduced activity, and lower energy expenditure.
10× more ghrelin sensitive when obeseObese LEAP2-KO mice responded to ghrelin at a dose 10 times lower than what was needed to stimulate eating in wild-type obese mice
What the researchers found
LEAP2 deletion sensitized mice to ghrelin's orexigenic and GH-releasing effects, with LEAP2-KO females on high-fat diet showing 15% more body weight, 18% more food intake, 42% more hepatic fat, and increased body length.
Why it matters
LEAP2 acts as a natural brake on ghrelin signaling. Understanding this balance could lead to new treatments for obesity (boosting LEAP2) or wasting conditions (blocking LEAP2 to increase appetite).
The numbers in context
Ghrelin sensitivity: 2x in lean, 10x in obese; GH 90.9% higher; c-fos 77-120% higher in arcuate/olfactory; females HFD: +15% weight, +18% food, +42% liver fat, +1.7% length, -13% O2, -9.5% heat, -49% locomotion
How the study worked
Generated first LEAP2-KO mouse line. Tested ghrelin-stimulated food intake, GH secretion, and brain c-fos activation. Monitored body weight, composition, energy expenditure, and locomotor activity over 16 weeks on high-fat or standard diet.
Who was studied
First LEAP2-knockout mice vs wild-type littermates on high-fat or standard diet over 16 weeks
What this study cannot tell us
Animal study in mice. Sex-specific effects (mainly in females) may complicate translation. High-fat diet effects were more pronounced than standard diet effects. Complete LEAP2 deletion is more extreme than physiological variation.
How to read the evidence
This is a well-designed preclinical study using the first LEAP2-knockout mouse model with comprehensive metabolic phenotyping. The study is thorough (multiple endpoints, both sexes, two diets, 16-week duration) but is limited to mice and the extreme scenario of complete LEAP-2 deletion.
When this study was published
Published in 2021, this was the first LEAP2-knockout study and remains a foundational reference for the LEAP-2/ghrelin field. Subsequent research has continued to explore LEAP-2's metabolic roles.
The bigger picture
This is the definitive loss-of-function study for LEAP-2, complementing the earlier gain-of-function work showing that LEAP-2 blocks ghrelin. By removing LEAP-2 entirely, the researchers proved it acts as a physiological brake on ghrelin signaling — not just a pharmacological curiosity. The dramatic sex differences (females affected much more than males) open new questions about how LEAP-2 interacts with sex hormones. The 'ghrelin resistance' seen in obesity (where ghrelin no longer stimulates appetite effectively) may be partly mediated by elevated LEAP-2 levels, and this study shows that removing LEAP-2 can restore ghrelin sensitivity even in obese mice.
Questions still open
- Why are female mice so much more affected by LEAP-2 deletion than males — does estrogen interact with LEAP-2/ghrelin signaling?
- Could LEAP-2 agonists become anti-obesity drugs, and would they work differently in men versus women?
- Is the 'ghrelin resistance' seen in human obesity caused by elevated LEAP-2, and could this be a therapeutic target?
Common questions
What happens when LEAP-2 is completely removed?
Could this lead to new obesity treatments?
Read the original research
LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.
Molecular metabolism, 53, 101327
Citation
Shankar, Kripa; Metzger, Nathan P; Singh, Omprakash; Mani, Bharath K; Osborne-Lawrence, Sherri; Varshney, Salil; Gupta, Deepali; Ogden, Sean B; Takemi, Shota; Richard, Corine P; Nandy, Karabi; Liu, Chen; Zigman, Jeffrey M. (2021). LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.. Molecular metabolism, 53, 101327. https://doi.org/10.1016/j.molmet.2021.101327