Unraveling Ghrelin: A Historical Journey to the Discovery of the Hunger Hormone

For decades, the existence of an endogenous ligand for the Growth Hormone Secretagogue Receptor (GHSR) remained elusive, despite the development of potent synthetic growth hormone secretagogues (GHSs). These synthetic compounds demonstrated robust stimulation of growth hormone (GH) release, yet the body's natural counterpart was unknown. This review meticulously chronicles the scientific efforts and breakthroughs that ultimately led to the identification and characterization of ghrelin as the endogenous ligand for GHSR.

The historical review highlights a series of pivotal discoveries. Early synthetic GHSs, such as GHRP-6, were shown to increase GH release by 2- to 5-fold in rat pituitary cells in vitro at concentrations as low as 10 nM. Subsequent in vivo studies in rats (n=10-12 per group) demonstrated that synthetic GHSs like MK-0677 could elevate plasma GH levels by 300-500% within 60 minutes following a single oral dose of 1 mg/kg. This robust activity strongly suggested the presence of a specific receptor. The most significant finding was the successful isolation and identification of ghrelin from rat stomach extracts in 1999, a 28-amino acid peptide that bound to the GHSR with an affinity of ~0.5 nM, demonstrating 10-fold higher potency than previously known synthetic GHSs in stimulating GH release. Further research revealed that ghrelin levels were significantly elevated during fasting (up to 2-fold increase) and rapidly decreased after feeding, indicating its crucial role in appetite regulation and energy homeostasis beyond just GH secretion.