Ghrelin: More Than a Natural GH Secretagogue and/or an Orexigenic Factor

E. Ghigo; F. Broglio; E. Arvat; M. Maccario; M. Papotti; G. Muccioli


Clin Endocrinol. 2005;62(1):1-17. 

In This Article

Summary and Introduction

Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin 'the' or just 'a' GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives.

Ghrelin is an acylated peptide produced predominantly by the stomach that has been discovered to be a natural ligand of the orphan growth hormone secretagogue receptor type 1a (GHS-R1a) (Smith et al., 1997; Kojima et al., 1999, 2001b; Korbonits et al., 2004; van der Lely et al., 2004). Like synthetic GHS, ghrelin possesses a strong GH-releasing effect both in animals and in humans (Kojima et al., 2001a; Korbonits et al., 2004). GHS receptors are expressed in the hypothalamus and pituitary gland, and also in other areas of the central nervous system (CNS) and in several peripheral tissues (Smith et al., 1997; Papotti et al., 2000; Gnanapavan et al., 2002). This GHS-R distribution is consistent with the GH-releasing effect of ghrelin and also with its broad endocrine and nonendocrine activities. In particular, ghrelin has been considered recently because of its stimulatory action on food intake and its modulatory effect on energy metabolism. However, ghrelin is more than simply a natural GH secretagogue and/or an orexigenic factor. The aim of this review is to provide a comprehensive overview of the wide spectrum of the actions of ghrelin.