Discovered in 1999 by Kojima and colleagues, ghrelin is unique among gut peptides in carrying an n-octanoyl modification on its serine-3 residue , an acylation that is essential for binding to and activating GHS-R1a. This acylation is catalysed by the enzyme ghrelin O-acyltransferase (GOAT). Circulating ghrelin exists in two main forms: acylated ghrelin (the biologically active form at GHS-R1a) and des-acyl ghrelin, which is more abundant in plasma and is now understood to have distinct physiological activity at receptors yet to be fully characterised.
Physiologically, ghrelin concentrations rise in the fasted state and fall following food intake, a pattern consistent with its established role as a peripheral hunger signal. At the hypothalamic level, ghrelin stimulates neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurones in the arcuate nucleus, promoting positive energy balance. Ghrelin also acts on the pituitary to stimulate growth hormone secretion, and is expressed in smaller quantities in the hypothalamus, pancreas, and other peripheral tissues, indicating broader physiological roles in glucose metabolism and gastrointestinal motility.
Several synthetic ghrelin analogues and GHS-R1a agonists have been investigated in clinical research settings. In Australia, no ghrelin-mimetic peptide analogue is approved by the Therapeutic Goods Administration (TGA) as a therapeutic good for general supply. Synthetic analogues sold for purposes such as performance enhancement or body composition are not approved therapeutic goods; supplying them without TGA approval is illegal under the Therapeutic Goods Act 1989 (Cth), and the TGA has taken enforcement action in this area. Any clinical or research use of such compounds requires appropriate regulatory authorisation.
Research into ghrelin's receptor pharmacology continues across academic institutions, with GHS-R1a recognised as a target of interest in multiple physiological contexts. As with all investigational peptide research, findings from preclinical and early-phase studies should be interpreted with caution given differences in bioavailability, receptor distribution, and species-specific physiology.
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