Without LEAP-2, Mice Become Super-Sensitive to Ghrelin — and Females Gain More Weight on a High-Fat Diet
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- 10× more ghrelin sensitive when obese Obese LEAP2-KO mice responded to ghrelin at a dose 10 times lower than what was needed to stimulate eating in wild-type obese mice
- Evidence Grade:
- 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.
- Study Age:
- 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.
- Original Title:
- LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.
- Published In:
- Molecular metabolism, 53, 101327 (2021)
- Authors:
- Shankar, Kripa(3), Metzger, Nathan P(4), Singh, Omprakash(2), 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
- Database ID:
- RPEP-05754
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
What happens when LEAP-2 is completely removed?
Mice without LEAP-2 become super-sensitive to ghrelin — the hunger hormone can stimulate eating at much lower doses than normal. Female mice on a high-fat diet gained significantly more weight, ate more, moved less, and accumulated 42% more fat in their livers. Males were mostly unaffected, suggesting LEAP-2's metabolic role has a strong sex-dependent component.
Could this lead to new obesity treatments?
Potentially. If LEAP-2 naturally dampens ghrelin's appetite-stimulating effects, then drugs that boost LEAP-2 activity could reduce hunger. Conversely, blocking LEAP-2 could help people with wasting conditions who need to eat more. The sex-specific findings suggest these treatments might work differently in men and women.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-05754APA
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
MLA
Shankar, Kripa, et al. "LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.." Molecular metabolism, 2021. https://doi.org/10.1016/j.molmet.2021.101327
RethinkPeptides
RethinkPeptides Research Database. "LEAP2 deletion in mice enhances ghrelin's actions as an orex..." RPEP-05754. Retrieved from https://rethinkpeptides.com/research/shankar-2021-leap2-deletion-in-mice
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.