PMID-10604470 – Ghrelin Discovery Growth Hormone Releasing Peptide from Stomach
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. "Ghrelin is a growth-hormone-releasing acylated peptide from stomach," Nature, 1999;402(6762):656-660.
Quick Reference
| Property | Value |
|---|---|
| PMID | 10604470 |
| DOI | 10.1038/45230 |
| Year | 1999 |
| Journal | Nature |
| Study Type | In vitro / Animal in vivo (discovery) |
| Evidence Level | V |
| Sample | Rat stomach tissue + in vivo rat GH assays |
| Peptide(s) Studied | Ghrelin |
Key Findings
- Identified ghrelin as a 28-amino acid peptide — the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a)
- Ghrelin is primarily produced by X/A-like enteroendocrine cells of the gastric oxyntic mucosa (stomach fundus)
- Ser3 residue is modified with an n-octanoyl (C8:0) fatty acid group — this acylation is essential for GH-releasing activity and receptor binding
- Intravenous administration of ghrelin potently stimulated GH release in rats in a dose-dependent manner
- Named "ghrelin" from the Proto-Indo-European root "ghre" meaning "to grow" — reflecting its GH-releasing function
- This discovery resolved the orphan receptor problem: GHS-R had been cloned in 1996 but its natural ligand was unknown until this study
- Established the stomach as an endocrine organ producing a hormone that directly regulates GH secretion from the pituitary
Study Design
Reverse pharmacology approach: used the cloned orphan receptor GHS-R1a to screen tissue extracts for endogenous ligands. Rat stomach extracts showed the highest activity. The active peptide was purified by HPLC, sequenced, and its structure confirmed by mass spectrometry. GH-releasing activity was validated by in vivo IV injection in rats with measurement of plasma GH levels.
Limitations
- Initial discovery in rat; human ghrelin subsequently confirmed with identical sequence
- GH-releasing activity measured acutely; chronic effects not assessed
- Focus on GH axis; appetite-stimulating properties not explored in this initial report
- Receptor binding assay conditions may not fully reflect in vivo complexity
Clinical Relevance
This Nature publication is one of the most cited papers in endocrinology and peptide biology. The discovery of ghrelin as the endogenous GHS-R1a ligand provided the mechanistic foundation for understanding why synthetic GH secretagogues (MK-677, GHRP-6, GHRP-2, ipamorelin, hexarelin) stimulate GH release. It established the gut-brain-pituitary axis concept and opened entirely new research areas in appetite regulation, metabolism, and neuroendocrine physiology. For the vault, understanding ghrelin is essential context for the entire GH Axis peptide category.
Related
#research #in-vitro #animal-in-vivo #evidence-level-V #gh-axis #ghrelin