Ghrelin is a rare case of a receptor being found before its hormone. In the 1980s, chemists built synthetic peptides that released growth hormone through an unknown receptor. In 1996 that receptor was cloned, and in 1999 researchers in Japan finally found the body’s own key for the lock, in the stomach. It turned out to do far more than release growth hormone: it is the body’s best-known hunger signal.
This guide explains what ghrelin is, how it was discovered, the unusual fatty-acid tag it needs, what it does, and how it connects to the GHRPs and ipamorelin studied in research today.
The short answer
- Ghrelin is a 28-amino-acid peptide hormone made mainly by endocrine cells in the stomach lining.
- It was discovered in 1999 by Masayasu Kojima, Kenji Kangawa and colleagues as the natural partner of the growth hormone secretagogue receptor, GHS-R1a.
- To activate that receptor it needs an unusual modification: an eight-carbon fatty acid, the octanoyl group, attached to its third amino acid by an enzyme called GOAT, identified in 2008.
- Ghrelin levels rise before meals and fall after eating. It stimulates appetite and triggers growth hormone release.
- Synthetic agonists of its receptor include the GHRPs and ipamorelin studied in research, and approved medicines such as macimorelin, a diagnostic test for adult growth hormone deficiency.
Ghrelin
Human acyl-ghrelin, 28 amino acids, octanoylated at serine 3
- G
- S
- S*
- F
- L
- S
- P
- E
- H
- Q
- R
- V
- Q
- Q
- R
- K
- E
- S
- K
- K
- P
- P
- A
- K
- L
- Q
- P
- R
S*: serine 3 carries the octanoyl fatty-acid group that the receptor requires. Read the sequence with our amino acid code chart.
- Made in
- Endocrine cells of the stomach lining
- Precursor
- 117-amino-acid preproghrelin
- Receptor
- GHS-R1a, a class A GPCR
- Key modification
- Octanoyl group on serine 3, added by GOAT
- Discovered
- 1999, Kojima, Kangawa and colleagues
Where the evidence stands
- Cell studies
- Animal studies
- Human studies
- Controlled trials (receptor drugs)
Human studies include ghrelin infusions; approved drugs act on its receptor.
A receptor in search of a hormone
- 1980sCyril Bowers and colleagues design small synthetic peptides that release growth hormone through a receptor distinct from the GHRH receptor. GHRP-6 is the best known; see our GHRP comparison.
- 1996Researchers at Merck clone that receptor and name it the growth hormone secretagogue receptor. Its natural ligand is unknown, so it is called an orphan receptor.
- 1999Masayasu Kojima, Kenji Kangawa and colleagues purify the missing hormone from rat stomach and report it in Nature. They name it ghrelin, from a root meaning “grow”, for its growth hormone-releasing action.
- 2008Two teams identify GOAT, the enzyme that attaches ghrelin’s fatty-acid tag.
This route to discovery, starting from a synthetic drug, finding its receptor and only then finding the natural hormone, is called reverse pharmacology. It means the GHRPs in today’s research catalogues were activating the ghrelin system years before anyone knew ghrelin existed.
The fatty-acid tag
Ghrelin is one of very few hormones modified with a fatty acid. An octanoyl group, an eight-carbon chain, is attached to the side chain of serine 3, and without it ghrelin cannot activate GHS-R1a. The enzyme responsible, ghrelin O-acyltransferase or GOAT, was identified in 2008 and is studied as a possible drug target in its own right.
Most ghrelin in the blood actually lacks the tag. This unacylated form, des-acyl ghrelin, does not activate GHS-R1a and is studied separately. Measuring the two forms correctly is one of the technical challenges of ghrelin research.
Ghrelin-receptor research peptides with Janoshik certificates.
Browse growth and signallingWhat ghrelin does
- Hunger. Ghrelin levels climb before meals and fall after eating, a pattern first reported in people in 2001. It acts on appetite-promoting neurons in the hypothalamus, which is why it is often called the hunger hormone.
- Growth hormone. Through GHS-R1a on the pituitary and hypothalamus, it triggers growth hormone release, working alongside GHRH; our growth hormone peptides map shows how the two systems fit together.
- Metabolism. It also influences stomach emptying and dampens insulin release, part of its role in signalling an energy shortfall.
GHS-R1a has an unusual property: it is partly active even with no hormone bound. That built-in activity makes the receptor a subject of study in its own right; our guide to how peptide receptors work explains the receptor family it belongs to.
Ghrelin vs the synthetic agonists
| Compound | What it is | Notable feature |
|---|---|---|
| Ghrelin | Natural 28-amino-acid hormone | Needs its octanoyl tag; short-lived in the body |
| GHRP-6 | Synthetic hexapeptide, 1980s | Contains D-amino acids; also affects appetite |
| GHRP-2 | Synthetic hexapeptide | More potent than GHRP-6 in early studies |
| Ipamorelin | Synthetic pentapeptide, 1998 | Released growth hormone without raising ACTH or cortisol in the study that introduced it |
The synthetic agonists share ghrelin’s receptor but not its structure. They are short, built partly from mirror-image D-amino acids, and need no fatty-acid tag; see our guide to D-amino acids. For a direct comparison of growth hormone secretagogues, read CJC-1295 vs ipamorelin.
GHRP-6The original ghrelin-receptor hexapeptideView product and COA
GHRP-2Potent synthetic hexapeptideView product and COA
IpamorelinSelective ghrelin-receptor agonistView product and COA
Ghrelin-receptor drugs
Several medicines act on the ghrelin receptor. Macimorelin, an oral agonist, was approved in the United States in 2017 as a test for adult growth hormone deficiency. Anamorelin has been approved in Japan for cancer cachexia, the severe wasting that can accompany cancer. In veterinary medicine, capromorelin is approved as an appetite stimulant for dogs. These are regulated products with their own approvals; research-grade ghrelin-receptor agonists are laboratory reagents, not substitutes for them.
Reasonably well established
- Ghrelin is the natural ligand of GHS-R1a and needs its octanoyl tag to activate it.
- It rises before meals and stimulates appetite and growth hormone release.
- Drugs acting on its receptor have reached approval for specific uses.
Open questions
- What des-acyl ghrelin does, given that it does not activate GHS-R1a.
- How ghrelin signalling changes in obesity and after weight loss.
- Whether GOAT inhibitors have practical uses.
Sourcing ghrelin-receptor agonists in Canada
Before ordering GHRP-6, GHRP-2, hexarelin or ipamorelin from any supplier, check that:
- The mass matches the specific peptide. GHRP-6 and GHRP-2 are both hexapeptides with similar names but different sequences and masses. See our HPLC testing guide.
- The certificate names your batch. Match the batch number on your vial to its report; our peptide COA guide explains how to read it.
- You understand what the powder contains. These peptides are basic and carry counter-ions; see our net peptide content guide.
Research use only. Pure Peptides Canada products are laboratory reagents, not for human or veterinary use. This article is general scientific education and is not medical, dosing or appetite-related advice.
Frequently asked questions
What is ghrelin?
Ghrelin is a 28-amino-acid peptide hormone made mainly in the stomach. It is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a) and is best known for stimulating appetite and growth hormone release.
Why is ghrelin called the hunger hormone?
Its blood levels rise before meals and fall after eating, and it acts on appetite-promoting neurons in the hypothalamus. Giving ghrelin increases food intake in animal and human studies.
How does ghrelin affect growth hormone?
Ghrelin activates GHS-R1a in the pituitary and hypothalamus, triggering growth hormone release. It works alongside growth hormone-releasing hormone, which acts on a different receptor.
What is the difference between acyl and des-acyl ghrelin?
Acyl-ghrelin carries an octanoyl fatty-acid group on serine 3, added by the enzyme GOAT, and is the form that activates GHS-R1a. Des-acyl ghrelin lacks the group, makes up most circulating ghrelin and does not activate that receptor.
How are GHRPs related to ghrelin?
GHRPs are synthetic peptides, developed in the 1980s, that activate the same receptor as ghrelin. They were used to find and clone the receptor in 1996, three years before ghrelin itself was discovered.
Are there approved drugs that act like ghrelin?
Yes. Macimorelin is approved in the United States as a diagnostic test for adult growth hormone deficiency, anamorelin is approved in Japan for cancer cachexia, and capromorelin is a veterinary appetite stimulant for dogs.
Ghrelin-receptor research peptides
GHRP-6, GHRP-2 and ipamorelin with Janoshik certificates, priced in Canadian dollars and shipped tracked from inside Canada.
References
- Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–660.
- Howard AD, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:974–977.
- Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387–396.
- Cummings DE, et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714–1719.
For laboratory research use only. Not for human or veterinary use. This article is educational and is not medical advice.