Ghrelin discovery: a decade after.

Since its discovery 12 years ago, intensive research has been performed on ghrelin. The significance of ghrelin as a growth hormone-releasing hormone, appetite regulator, energy conservator and sympathetic nerve suppressor has now been well established. In this short essay, we summarize the history of the discovery of ghrelin.

Discovery of ghrelin o-acyltransferase.

Ghrelin is a gut hormone with potent orexigenic and growth hormone release stimulatory effects, and is the first known endogenous ligand of the growth hormone secretagogue receptor. A notable feature of ghrelin is that it carries an acyl group, in most cases an octanoyl group, in the third serine. While it has been shown that the acylation is critical for the majority of ghrelin functions, the mechanisms of acylation of ghrelin remained poorly understood. In 2008, it was discovered that ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylating ghrelin. GOAT is highly conserved from zebrafish to humans. It is most abundant in the stomach and pancreas. GOAT mRNA expression is regulated by energy balance, being upregulated by energy restriction and downregulated by energy abundance. GOAT attenuation using synthetic inhibitors enhances insulin secretion and reduces body weight. GOAT inhibitors are currently being developed for the treatment of metabolic disorders. In addition to its ghrelin mediated effects, GOAT is also known to directly regulate bile acid secretion. The discovery of GOAT helped to redefine the ghrelin research field and enabled the development of another target molecule for potential therapies aimed to prevent/treat diabetes and obesity.

History to the discovery of ghrelin.

The most important initial historical time points in the development of the enlarging ghrelin system were 1973, 1976, 1982, 1984, 1990, 1996, 1998, and 1999. At these respective times, the following occurred sequentially: isolation of somatostatin, discovery of unnatural growth-hormone-releasing peptides (GHRPs), isolation of growth-hormone-releasing hormone (GHRH), hypothesis of a new natural GHRP different from GHRH, GHRP+GHRH synergism in humans, discovery of the growth hormone secretagogue GHS/GHRP receptor, cloning of the receptor, and finally, isolation and identification of the new natural endogenous GHRP ghrelin. To understand the pharmacology and probably also the physiological regulation of growth hormone (GH) secretion, an important finding was that GHRP increased pulsatile GH secretion in children as well as normal younger and older men and women. This requires endogenous GHRH secretion, even though GHRP alone substantially releases GH from the pituitary in vitro without the addition of GHRH. Unnatural GHRP gave rise to natural GHRP ghrelin because of many talented researchers worldwide. GHRP was first envisioned to be an analog of GHRH but, from comparison of the activity of GHRH and GHRPs between 1982 and1984, it was hypothesized to reflect the activity of a new hormone regulator of GH secretion yet to be isolated and identified. Intravenous bolus GHRP releases more GH than GHRH in humans, but the reverse occurs in vitro. GHRPs are pleiotropic peptides with major effects on GH, nutrition, and metabolism, especially as an additional hormone in combination with GHRH as a new regulator of pulsatile GH secretion. The first indication of pleiotropism was an increase of food intake by GHRP. A major reason for the prolonged initial interest in the GHRPs has been its similar, yet different and complementary, action with GHRH on GH regulation and secretion. Particularly noteworthy is the variable chemistry of the GHRPs. They consist of three major chemical classes, including peptides, partial peptides, and nonpeptides, and all probably act via the same receptor and cellular mechanisms. Generally, most GHRPs have been active by all routes of administration, intravenously (iv), subcutaneously (sc), orally, intranasally, and intracerebroventricularly (icv), which supports their possible broad future clinical utility. From evolutionary studies starting with the zebrafish, the natural receptor and hormone have been present for hundreds of years, underscoring the fundamental evolutionary and functional importance of the ghrelin system. GHRPs were well established to act directly on both the hypothalamus and pituitary several years before the GHS receptor assay (Howard et al., 1996; Smith et al., 1996; Van der Ploeg et al., 1998). Finally, the ghrelin chemical isolation and identification was accomplished surprisingly from the stomach, which is the major site but not the only site, for example, the hypothalamus (Bowers, 2005; Kojima et al., 1999; Sato et al., 2005). Ghrelin was isolated and identified by Kojima and Kangawa et al. in 1999. A primary action of GHRPs continues to concern GH secretion and regulation, but increasingly this has included direct and indirect effects on nutrition and metabolism as well as a variety of other actions which may be pharmacological and/or physiological. Possible continuing and expanding roles of this new hormonal receptor include the central nervous system as well as the cardiovascular, renal, gastrointestinal, pancreatic, immunological, and anti-inflammatory systems. Our basic and clinical studies have mainly involved effects on GH regulation and secretion and this relationship to metabolism. So far in our studies, the actions of GHRPs and ghrelin on GH secretion and regulation in rats and probably in humans have generally been the same. A current objective is the incorporation of ghrelin into the diffuse endocrine hormonal system especially via GH.