Blocking ghrelin receptors with the peptide LEAP2 during pregnancy or early life altered liver glucose metabolism in rats at puberty, revealing how early peptide signaling programs lifelong metabolic function.
Liver PEPCK significantly alteredPerinatal LEAP2 exposure changed expression of a key liver glucose-production enzyme at puberty, even without body weight changes
What the researchers found
Blocking ghrelin receptor (GHSR) signaling during the perinatal period with LEAP2 (a natural ghrelin-blocking peptide) altered liver metabolism and glucose regulation in rats at puberty. LEAP2 injections during pregnancy or early postnatal life significantly impacted liver PEPCK expression — a key enzyme in glucose production — and affected glucose homeostasis in a sex- and timing-dependent manner.
Importantly, these metabolic effects occurred without changes in body weight or food intake, suggesting that early-life ghrelin signaling programs metabolic function in ways that only become apparent later in development. The authors note these effects may be the beginning of larger metabolic imbalances that could emerge in adulthood.
Why it matters
LEAP2 has emerged as ghrelin's natural 'off switch' — a peptide that blocks ghrelin's effects. This study reveals that disrupting ghrelin signaling during critical developmental windows with LEAP2 has lasting metabolic consequences, particularly in the liver. This matters for understanding how early-life peptide signaling programs lifelong metabolic health, and raises questions about whether interventions targeting the ghrelin system (including MK-677, a popular growth hormone secretagogue) could have unintended developmental effects if used during pregnancy or infancy.
The numbers in context
LEAP2[1-14] fragment used · 2 experimental models (pregnancy + postnatal) · MK-677 used as comparator · liver PEPCK expression significantly altered · sex-dependent glucose effects · no weight or food intake changes
How the study worked
Animal study using two rat models: (1) LEAP2[1-14] peptide injections in pregnant female rats, and (2) postnatal modulation of ghrelin receptors with either LEAP2[1-14] or MK-677 in offspring. Researchers measured body weight, food intake, glucose homeostasis, and liver enzyme expression (PEPCK) in the offspring at puberty.
Who was studied
Rat pups exposed to LEAP2[1-14] or MK-677 during perinatal period, assessed at puberty
What this study cannot tell us
Rat model — early-life metabolic programming may differ between species. The study used a truncated LEAP2 fragment [1-14] rather than full-length LEAP2. Effects at puberty were described as 'not expressive' — suggesting they may be subtle early signals rather than robust findings. Adult outcomes were not assessed. Specific glucose homeostasis data and effect sizes were not detailed in the abstract.
How to read the evidence
Preliminary evidence from a rat study with subtle effects described as 'not expressive.' While the study design is sound and uses two developmental models, the findings suggest early-stage metabolic changes rather than definitive disease outcomes. The abstract notes these may be 'the beginning' of larger effects that need longer follow-up.
When this study was published
Published in 2024. This is very recent work in the rapidly evolving LEAP2 field. LEAP2 was only identified as ghrelin's endogenous antagonist in 2018, so developmental studies like this are pioneering.
The bigger picture
LEAP2 was discovered in 2018 as ghrelin's natural antagonist and has quickly become one of the most studied peptides in metabolism research. This study adds a developmental dimension: LEAP2 isn't just relevant for adult appetite and glucose control — it plays a programming role during early life. This has implications for understanding how maternal peptide levels during pregnancy might influence offspring metabolic health, and raises caution about using ghrelin-targeting compounds (like MK-677) in contexts where they could affect developing organisms.
Questions still open
- Do these early metabolic programming effects worsen into full metabolic disease in adulthood?
- Could maternal ghrelin or LEAP2 levels during pregnancy predict metabolic risk in offspring?
- Does MK-677 use during or around pregnancy pose developmental metabolic risks?
Common questions
What is LEAP2 and why is it important?
Should people using MK-677 be concerned about this study?
Read the original research
GHSR signalling in perinatal phases is involved in liver metabolism at puberty.
The Journal of endocrinology, 263(1)
Citation
Ferreira-Junior, Marcos Divino; Cavalcante, Keilah Valéria Naves; Xavier, Carlos Henrique; Vanzela, Emerielle Cristine; Boschero, Antonio Carlos; Matafome, Paulo; Gomes, Rodrigo Mello. (2024). GHSR signalling in perinatal phases is involved in liver metabolism at puberty.. The Journal of endocrinology, 263(1). https://doi.org/10.1530/JOE-24-0039