CB1 receptor blockade stimulated gastric production and release of nesfatin-1, a hormone that promotes satiety, through the mTOR/S6k signaling pathway, revealing how the peripheral cannabinoid system regulates food intake via the stomach.
Read this if you want to understand how the cannabinoid system in the gut regulates appetite signals.
Stomach CB1 blockade increased the satiety hormone nesfatin-1 through mTOR signaling
What the researchers found
When rats were treated with the CB1 inverse agonist rimonabant, food intake decreased and gastric secretion of Nucb2/nesfatin-1 (a satiety peptide) increased. Circulating nesfatin-1 levels in the blood also rose.
Rimonabant activated the mTOR signaling pathway in the stomach, as shown by increased phosphorylated mTOR. When mTOR was blocked with rapamycin, rimonabant could no longer stimulate nesfatin-1 release, confirming that the mTOR/S6k pathway mediates this effect.
The same results were confirmed using a second CB1 antagonist (AM281), strengthening the conclusion that this is specifically a CB1-mediated mechanism.
Why it matters
This study reveals a specific mechanism by which the cannabinoid system in the stomach, not the brain, regulates appetite. The mTOR pathway connection is important because mTOR is a central cellular energy sensor. This peripheral circuit could be targeted to reduce appetite without affecting the brain.
The numbers in context
Rimonabant increased gastric nesfatin-1 secretion and circulating levels. Rapamycin blocked rimonabant's effect on nesfatin-1 release. mTOR phosphorylation increased in gastric tissue after CB1 blockade. Confirmed with second CB1 antagonist AM281.
How the study worked
Rats received rimonabant, rapamycin, rapamycin plus rimonabant, or vehicle. Gastric tissue was analyzed for Nucb2 mRNA, protein content, and mTOR pathway activation. Gastric secretomes (collected from tissue explants) and plasma were assayed for nesfatin-1 levels.
What this study cannot tell us
Animal study using injected drugs. Rimonabant was withdrawn from human use due to psychiatric side effects. The gastric mTOR-nesfatin pathway may differ between rats and humans. Only acute effects were measured.
How to read the evidence
Animal study with pharmacological confirmation using two CB1 antagonists and pathway inhibition. Strong mechanistic data but animal only.
When this study was published
Published in 2017. Peripheral cannabinoid control of appetite hormones continues to be investigated.
The bigger picture
The stomach is not just a digestive organ; it is an endocrine organ that sends satiety signals to the brain. This study shows the cannabinoid system regulates one of these signals (nesfatin-1) through a specific cellular pathway. Understanding this circuit could lead to appetite-controlling medications that work peripherally, avoiding the psychiatric side effects of brain-acting CB1 blockers.
Questions still open
- Would peripherally restricted CB1 blockers activate this same gastric nesfatin pathway? Does chronic cannabis use suppress gastric nesfatin-1, contributing to the appetite-stimulating effects of THC? Could nesfatin-1 itself be developed as an appetite suppressant?
Common questions
What is nesfatin-1?
Does this explain the "munchies"?
Read the original research
Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway.
World journal of gastroenterology, 23(35), 6403-6411
Citation
Folgueira, Cintia; Barja-Fernandez, Silvia; Prado, Laura; Al-Massadi, Omar; Castelao, Cecilia; Pena-Leon, Veronica; Gonzalez-Saenz, Patricia; Baltar, Javier; Baamonde, Ivan; Leis, Rosaura; Dieguez, Carlos; Pagotto, Uberto; Casanueva, Felipe F; Tovar, Sulay A; Nogueiras, Ruben; Seoane, Luisa M. (2017). Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway.. World journal of gastroenterology, 23(35), 6403-6411. https://doi.org/10.3748/wjg.v23.i35.6403
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