Motilin, a gut peptide hormone from the ghrelin family, was shown for the first time to directly stimulate food intake by signaling through the vagus nerve to appetite centers in the brain.
First direct proofMotilin was confirmed as a direct appetite stimulator, signaling from the gut through the vagus nerve to hunger centers in the brainstem and hypothalamus
What the researchers found
Using house musk shrews (Suncus murinus) — one of the few small mammals that produce motilin — researchers demonstrated for the first time that the peptide hormone motilin directly stimulates food intake linked to gastric motility. Plasma motilin levels were elevated during phase III contractions of the migrating motor complex, and food intake was higher during these contractions. Intravenous motilin administration increased feeding during phase I (though less potently than ghrelin).
Critically, motilin's feeding effect was completely abolished by vagotomy, proving the signal travels through the vagus nerve. Motilin also activated appetite-regulating neurons in the brainstem and hypothalamus, including neuropeptide Y neurons in the arcuate nucleus.
Why it matters
Motilin has long been known to trigger stomach contractions and hunger sensations, but direct evidence that it regulates food intake was lacking — partly because rats and mice lack functional motilin genes. This study fills that gap, establishing motilin as a genuine appetite-regulating peptide hormone and identifying the neural pathway (vagus nerve → brainstem → hypothalamus) through which it works. This positions motilin as a potential therapeutic target for appetite disorders, adding to the growing toolkit of gut peptides that could be harnessed for metabolic medicine.
The numbers in context
Phase III vs Phase I contractions compared · Motilin feeding effect weaker than ghrelin · Vagotomy abolished motilin-induced feeding · c-Fos activation in area postrema, NTS, and arcuate nucleus · NPY neurons activated
How the study worked
Researchers simultaneously monitored gastric contractions and food intake in conscious house musk shrews. Plasma motilin levels were measured during different phases of the migrating motor complex. Intravenous motilin and ghrelin were administered during phase I contractions to test feeding effects. Vagotomy was performed to test nerve dependency. Brain c-Fos immunohistochemistry identified activated neurons in appetite-regulating brain regions.
Who was studied
House musk shrews (Suncus murinus), a small mammal species that produces functional motilin
What this study cannot tell us
The study used Suncus murinus (house musk shrew) rather than a more commonly studied animal, and results may not directly translate to humans. The relationship between motilin and food intake in humans requires clinical confirmation. The study focused on acute motilin administration rather than chronic effects. The comparison with ghrelin was limited and quantitative dose-response data were not fully detailed in the abstract.
How to read the evidence
This is a preclinical animal study using a non-traditional model organism (house musk shrew). It was published in PNAS, a high-impact journal, and provides mechanistic evidence including vagotomy controls and brain activation mapping. However, translation to human appetite regulation requires further study.
When this study was published
Published in 2025, this is very recent work that fills a long-standing gap in our understanding of motilin's role in appetite regulation. It may catalyze new research into motilin-based therapeutics.
The bigger picture
The discovery that motilin directly regulates appetite through a defined neural pathway adds a new player to the gut-brain peptide axis alongside ghrelin, GLP-1, and PYY. As the pharmaceutical industry develops peptide-based treatments for obesity and appetite disorders, understanding motilin's role could lead to new therapeutic approaches — or help explain why some patients with gastric motility disorders also have appetite dysregulation.
Questions still open
- Could motilin receptor agonists or antagonists be developed as treatments for appetite disorders?
- How does motilin interact with GLP-1 and ghrelin signaling in the broader appetite regulation system?
- Do patients with gastroparesis or other motility disorders have altered motilin-mediated appetite regulation?
Common questions
What is motilin and how is it related to ghrelin?
Why couldn't scientists study motilin in regular lab mice?
Read the original research
Motilin stimulates food intake linked to gastric motility in Suncus murinus: Simultaneous recordings of food intake and gastric motility in the conscious state.
Proceedings of the National Academy of Sciences of the United States of America, 122(28), e2424363122
Citation
Huang, Jin; Watanabe, Ayumi; Kanaya, Moeko; Gomi, Ayano; Yokoyama, Haruka; Ishii, Hikari; Nakamura, Yusuke; Azuma, Morio; Konno, Norifumi; Kaiya, Hiroyuki; Sakai, Takafumi; Sakata, Ichiro. (2025). Motilin stimulates food intake linked to gastric motility in Suncus murinus: Simultaneous recordings of food intake and gastric motility in the conscious state.. Proceedings of the National Academy of Sciences of the United States of America, 122(28), e2424363122. https://doi.org/10.1073/pnas.2424363122