Ghrelin

What is Ghrelin?

Ghrelin is a 28-amino-acid acylated peptide hormone secreted by X/A-like enteroendocrine cells in the gastric mucosa. Discovered in 1999 by Kojima and colleagues at the National Cardiovascular Center Research Institute in Japan, it is:

• The only known endogenous orexigenic (appetite-stimulating) hormone in humans
• The natural ligand of the growth hormone secretagogue receptor (GHSR-1a) — the same receptor activated by synthetic agonists like GHRP-2, GHRP-6, ipamorelin, MK-677 (ibutamoren), hexarelin, and macimorelin
• A potent stimulator of GH secretion from anterior pituitary somatotrophs
• A major regulator of energy balance, gastric motility, and reward circuits

Ghrelin is research-only as a therapeutic — there are no approved drugs that are native ghrelin. The closely related synthetic agonists (GHRPs, MK-677, anamorelin, macimorelin) are the clinically and commercially relevant molecules in this pathway.

Structure — The Octanoyl Modification

Ghrelin's defining structural feature is a n-octanoyl modification at serine 3 — an 8-carbon fatty acid covalently attached via an ester bond. This modification is absolutely required for bioactivity at GHSR-1a:

• Acyl-ghrelin — the active hormone, with octanoyl group
• Des-acyl ghrelin — the deacylated form, which lacks GHSR-1a binding but has its own emerging biology

The acylation is performed by ghrelin O-acyltransferase (GOAT), a unique membrane-bound acyltransferase that uses medium-chain fatty acyl-CoA as substrate. GOAT is itself a research target — inhibition of GOAT could pharmacologically reduce active ghrelin levels.

Functions

Appetite and food intake:

• Released in fasting state, suppressed postprandially
• Stimulates appetite via NPY/AgRP neurons in arcuate nucleus
• The most potent endogenous appetite-stimulating signal known

Growth hormone:

• Strongly stimulates GH release from somatotrophs
• Synergizes with GHRH

Reward and motivation:

• Activates dopaminergic reward circuits in ventral tegmental area
• Implicated in food-related and addiction-related reward

Other functions:

• Slows gastric emptying (paradoxical given its appetite-stimulating effect)
• Modulates insulin secretion
• Cardioprotective effects (debated)
• Anti-inflammatory effects in some tissues

Research and Clinical Investigation

Native acyl-ghrelin has been studied in:

• Cachexia — cancer-related, COPD, heart failure, anorexia nervosa
• Functional dyspepsia and gastroparesis — leveraging its prokinetic effects
• Anorexia nervosa — appetite stimulation potential
• Frailty/sarcopenia — GH release plus appetite stimulation

In Japan, anamorelin (a non-peptide ghrelin receptor agonist) has been approved for cancer cachexia. In the US and EU, no ghrelin receptor agonists are approved for cachexia indications.

Distinction from Synthetic GHSR-1a Agonists

The synthetic agonists were originally developed before ghrelin was discovered — chemists were optimizing molecules that activated a "GH secretagogue receptor" of unknown endogenous ligand. The 1999 discovery of ghrelin filled in the missing endogenous ligand.

Place in Research

Native ghrelin remains widely used in research to study:

• GHSR-1a biology
• Appetite regulation circuits
• GH secretion physiology
• Gastric motility
• Reward and addiction

It is sold by research chemical suppliers as the acylated active form. Note that the octanoyl modification is unstable; ghrelin must be carefully handled and stored to preserve bioactivity in research applications.