The Discovery of Ghrelin
| Category | Research |
|---|---|
| Also known as | ghrelin history, hunger hormone discovery, Kojima ghrelin |
| Last updated | 2026-04-14 |
| Reading time | 3 min read |
| Tags | historyghrelinappetitegrowth-hormonestomach |
Overview
Ghrelin is a 28-amino-acid peptide hormone produced mainly by endocrine cells in the gastric fundus. It was identified in 1999 by Masayasu Kojima, Kenji Kangawa, and colleagues at the National Cardiovascular Center Research Institute in Suita, Japan, as an endogenous ligand for the growth hormone secretagogue receptor (GHSR), a receptor whose natural activator had been sought for several years.
The hormone owes its name to the proto-Indo-European root "ghre-," meaning "to grow," reflecting its role in releasing growth hormone from the pituitary. Ghrelin quickly became better known, however, for its orexigenic effects ā it stimulates appetite, food intake, and body weight gain when administered experimentally. Circulating levels rise before meals and fall after eating, supporting its characterization as a "hunger signal."
A distinctive feature of ghrelin is its obligatory octanoyl modification: an eight-carbon fatty acid is attached to the third amino acid (a serine residue) by the enzyme ghrelin O-acyl transferase (GOAT). This acylation is required for binding to GHSR and has become a target for novel pharmacological approaches to obesity and metabolic disease.
Key People
- Masayasu Kojima: First author of the 1999 Nature paper reporting ghrelin's identification.
- Kenji Kangawa: Senior author and longtime leader of Japanese peptide-hormone research.
- Cyril Bowers: American endocrinologist whose work on synthetic growth hormone releasing peptides set the stage for identifying GHSR and its natural ligand.
- Aart J. van der Lely: European endocrinologist who has contributed extensively to clinical ghrelin research.
Timeline
- 1976: Bowers identifies synthetic growth hormone releasing peptides (GHRPs).
- 1996: The GHSR is cloned, but its natural ligand remains unknown.
- 1999: Kojima and colleagues identify ghrelin as the endogenous GHSR ligand.
- 2000s: Rapid expansion of research linking ghrelin to appetite, metabolism, and reward.
- 2008: GOAT enzyme is identified, explaining the octanoyl modification.
- 2010sā2020s: Development of ghrelin receptor agonists and antagonists for clinical use.
Background
The search for ghrelin illustrates the "orphan receptor" strategy in modern pharmacology. By the 1990s, molecular biology had identified numerous receptors with no known natural ligand. For GHSR, extensive work with synthetic GHRPs (such as GHRP-2 and GHRP-6) suggested that a natural hormone must exist. Kojima's laboratory used a calcium-mobilization assay in GHSR-expressing cells to screen tissue extracts, ultimately tracing activity to stomach tissue ā a surprising source for a growth-hormone-releasing factor.
The discovery also tied together disparate threads in endocrinology. Growth hormone physiology had been centered on the hypothalamus, where growth hormone releasing hormone and somatostatin govern pituitary output. Ghrelin added a peripheral, meal-related input to the system and linked gut-derived signals with central control of growth and energy balance.
Modern Relevance
Ghrelin has become a central concept in appetite research. Clinical observations, such as the dramatic fall in ghrelin levels after Roux-en-Y gastric bypass surgery, have reinforced its role in energy homeostasis. Pharmaceutical programs have pursued both ghrelin mimetics (e.g., anamorelin for cancer cachexia, relamorelin for gastroparesis) and ghrelin antagonists for obesity and metabolic disease.
Ghrelin research has also expanded into non-metabolic territory ā learning and memory, cardiovascular function, stress responses, and addiction. Although these directions are still evolving, they illustrate how a single peptide, once discovered, can reshape multiple fields of physiology. For a broader context, see glp1-research and leptin-discovery.
Related Compounds
Related entries
- History of Growth Hormone Researchā An overview of the discovery, purification, and recombinant production of growth hormone over the twentieth century.
- The Discovery of Leptinā Leptin, the hormone encoded by the ob gene, was cloned in 1994 by Jeffrey Friedman and colleagues and reshaped obesity research.
- History of Neuropeptide Yā Neuropeptide Y, one of the most abundant neuropeptides in the brain, was isolated by Tatemoto in 1982 at the Karolinska Institute.