At the Cutting EdgeGhrelin and reproduction: a novel signal linking energy status and fertility?☆
Introduction
Identification of ghrelin, in late 1999, as the natural ligand of the growth hormone (GH) secretagogue receptor (GHS-R) was the end-point of a long search for the endogenous counterpart of a large family of peptidyl and non-peptidyl synthetic compounds, globally termed GH secretagogues (GHS), with ability to elicit GH release in vivo and in vitro in a wide spectrum of species, including humans (Casanueva and Dieguez, 1999a, Kojima et al., 1999, Kojima et al., 2001). The functional ghrelin peptide results from the cleavage of a precursor form, the prepro-ghrelin, which is composed of 117 amino acids. In the human and rat, the mature ghrelin peptide consists of 28 amino acids, with divergence in two residues only (Kojima et al., 1999). Even in non-mammalian species, such as chicken, sequence homology is rather high, with 54% identity with human ghrelin (Kaiya et al., 2002). In the rat, a second form of the peptide, termed des-Gln(14)-ghrelin, has been described. Its biological activity and sequence are identical to ghrelin, except for the lack of one glutamine in position 14 (Hosada et al., 2000a). It is apparent, however, that this variant is present only in low amounts in the stomach, indicating that 28-aminoacid ghrelin is the main active form of the molecule (Hosada et al., 2000b). A unique feature of ghrelin molecule is the addition of an n-octanoyl group at Ser3, which is essential for its biological activity (Kojima et al., 1999). Such a post-translational modification (acylation) is the first reported in a secreted protein (Gualillo et al., 2003), although acyl modifications had been previously observed in G proteins and membrane-bound receptors. The enzymatic system responsible for acylation of ghrelin as well as the biological roles, if any, of des-acyl ghrelin (whose concentration in plasma largely exceeds that of mature ghrelin) remain largely unknown.
The biological actions of ghrelin are mostly conducted through interaction with its specific cell surface receptor, namely the GHS-R. The cognate ghrelin receptor belongs to the large family of G-protein coupled, seven transmembrane domain receptors (Howard et al., 1996, McKee et al., 1997, Smith et al., 1997). This receptor is highly expressed at central neuroendocrine tissues such as the pituitary and hypothalamus (Guan et al., 1997). Two GHS-R subtypes, generated by alternative splicing of a single gene, have been described: the full-length type 1a receptor and the truncated GHS-R type 1b (Howard et al., 1996, McKee et al., 1997). The GHS-R1a is the functionally active, signal transducing form of the receptor. In contrast, the GHS-R1b lacks the transmembrane domains 6 and 7, and it is apparently devoid of high-affinity ligand binding and signal transduction capacity (Howard et al., 1996). Thus, its functional role, if any, remains unclear. In addition, evidences for GHS-R-independent biological actions of ghrelin as well as of synthetic GHSs have been presented recently (Baldanzi et al., 2002, Ghe et al., 2002).
Section snippets
Ghrelin: central and peripheral actions
In recent years, a large body of evidence has demonstrated that the biological actions of ghrelin are much wider than those originally anticipated. Indeed, a striking feature of ghrelin is its widespread pattern of expression (Gualillo et al., 2003, Korbonits et al., 2004, van der Lely et al., 2004). Notably, ghrelin was originally identified in the stomach, which is by far the major source of circulating ghrelin, accounting for at least two-thirds of its plasma levels (Kojima et al., 2001,
Neuroendocrine integrators: the case of leptin
Recent advances in our knowledge on the neuroendocrine networks controlling different pivotal body functions have help to identify close connections between the systems governing somatic growth, energy balance and reproduction. Indeed, such a link had been long anticipated on the basis of the well-known need of sufficient energy stores for proper pubertal development, growth and fertility (Casanueva and Dieguez, 1999b). However, only recently, identification of the molecular signals responsible
Ghrelin and reproduction
As stated above, it is highly probable that additional neuroendocrine integrators may cooperate with leptin in the joint control of energy balance and reproduction. The data so far available make it tempting to speculate that ghrelin might be a candidate for such a physiological function. Indeed, leptin and ghrelin share some relevant functional features, as both molecules are peripheral factors involved in the control of food intake and the somatotropic axis. Moreover, leptin and ghrelin have
Ghrelin and reproduction: future perspectives and conclusions
Identification of ghrelin has been a major breakthrough in the field of neuroendocrinology. From a methodological point of view, its discovery illustrates a clear example of the usefulness of ‘reverse’ pharmacology and orphan receptor strategies in the search for potentially relevant endogenous ligands. From a physiological standpoint, cloning of ghrelin has forced us to revisit the accepted models of central control of GH secretion. In addition, ghrelin has turned out to be a rather ubiquitous
Acknowledgements
The authors are indebted to C. Dieguez, J. Toppari, E. Aguilar and L. Pinilla for helpful discussions during preparation of this manuscript. Experimental work conducted in the authors’ laboratory was supported by grants BFI 2000-0419-CO3-03 and BFI 2002-00176 from DGESIC (Ministerio de Ciencia y Tecnología, Spain), and EU research contract EDEN QLK4-CT-2002-00603.
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This work was supported by grants BFI 2000-0419-CO3-03 and BFI 2002-00176 from DGESIC (Ministerio de Ciencia y Tecnología, Spain), and EU research contract EDEN QLK4-CT-2002-00603.