Ghrelin

Ghrelin is a 28-amino acid acylated peptide hormone primarily secreted by oxyntic cells in the gastric fundus. It is the only known circulating peptide that stimulates appetite (orexigenic). Ghrelin is also the endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a), triggering pulsatile GH release. Its n-octanoyl modification at Ser-3 — added by the enzyme GOAT — is essential for GHSR binding and appetite stimulation. MK-677 (ibutamoren) was developed as a non-peptide oral ghrelin mimetic.

Ghrelin binds GHSR-1a, a constitutively active GPCR expressed in the hypothalamic arcuate nucleus, pituitary, and throughout the brain. Receptor activation stimulates GH release from pituitary somatotrophs via PLC-dependent signaling and activates hypothalamic NPY/AgRP neurons to increase food intake. Ghrelin also promotes reward-driven eating via dopamine release in the mesolimbic pathway (VTA, nucleus accumbens). Unacylated ghrelin (desacyl-ghrelin) circulates at higher levels and may have opposing metabolic effects through non-GHSR pathways.

Ghrelin rises sharply before meals and falls postprandially, establishing it as a hunger signal. It is suppressed by caloric restriction in a manner that may undermine long-term weight loss. GH secretagogue research led to MK-677 (ibutamoren), an oral GHSR agonist that increases GH and IGF-1 over 24 hours in Phase 2 studies. Ghrelin receptor antagonists are being studied for obesity and addiction. GOAT (ghrelin O-acyltransferase) inhibitors are a therapeutic target to selectively suppress acyl-ghrelin without affecting desacyl-ghrelin.

Peptides commonly paired with Ghrelin for synergistic effects.