Ghrelin

Discovery and Source

Ghrelin was identified in 1999 by Kojima and colleagues through bioassay-guided purification of rat stomach extracts stimulating growth hormone release from anterior pituitary cells. The name derives from the Proto-Indo-European root “ghre,” meaning “to grow.” Ghrelin-producing X/A-like enteroendocrine cells are concentrated in the gastric fundus oxyntic glands, accounting for approximately 80% of circulating ghrelin. Additional sources include the duodenum, jejunum, pancreas, hypothalamus, and placenta, though their contribution to plasma levels is minor.

Structure and Octanoylation

Ghrelin consists of 28 amino acids with the sequence: Gly-Ser-Ser(Oct)-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Ala-Gln-Lys-Pro-Pro-Ala-Leu-Gln-Gly-Arg-Val-Arg-Gln-Glu-Asp-Lys-His-Ser-Lys-NH2. The defining post-translational modification is O-octanoylation of Ser3, catalyzed by ghrelin O-acyltransferase (GOAT), a membrane-bound O-acyltransferase family member. This medium-chain fatty acid acylation is essential for receptor binding; unacylated ghrelin, which constitutes the majority of circulating ghrelin, does not activate the growth hormone secretagogue receptor. GOAT expression is regulated by metabolic status, linking ghrelin acylation to nutritional state.

Receptor Signaling

Ghrelin activates the growth hormone secretagogue receptor (GHSR), a constitutively active Gq-coupled G protein-coupled receptor. GHSR is expressed in the hypothalamus (arcuate nucleus, ventromedial hypothalamus), pituitary, hippocampus, and various peripheral tissues. Receptor activation stimulates growth hormone release from somatotrophs, increases intracellular calcium in hypothalamic neurons, and activates AMPK in peripheral tissues. The constitutive activity of GHSR in the absence of ligand may contribute to its physiological role in basal growth hormone secretion.

Appetite Stimulation and Energy Balance

Ghrelin is the only known peripherally produced orexigenic hormone. Circulating ghrelin levels rise sharply before meals and fall rapidly postprandially, with carbohydrate-rich meals producing the greatest suppression. In the arcuate nucleus, ghrelin activates NPY/AgRP orexigenic neurons through GHSR, stimulating food intake and reducing energy expenditure. Ghrelin signaling also modulates mesolimbic dopamine reward pathways, promoting the hedonic value of food. Exogenous ghrelin administration robustly stimulates feeding in both lean and obese subjects.

Growth Hormone Secretion

Ghrelin is the most potent known stimulator of growth hormone release, acting both directly on pituitary somatotrophs and indirectly through hypothalamic GHRH neuron activation. The physiological significance of ghrelin-mediated growth hormone secretion during fasting may relate to metabolic adaptation, promoting lipolysis and protein conservation during energy deficit.

Clinical Implications

Ghrelin dysregulation has been implicated in Prader-Willi syndrome, anorexia nervosa, and obesity. Ghrelin-based therapies are under development for cachexia, post-surgical appetite restoration, and growth hormone deficiency. GHSR antagonists are being investigated as potential anti-obesity agents, though the pleiotropic effects of ghrelin signaling complicate therapeutic targeting.

References

Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660.
Kojima M, Kangawa K. Ghrelin: structure and function. Physiological Reviews. 2005;85:495-522.
Muller TD, Nogueiras R, Andermann ML, et al. Ghrelin. Molecular Metabolism. 2015;4:437-460.