Ghrelin: more than a new frontier in neuroendocrinology

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as natural ligand of the growth hormone secretagogue receptor (GHS-R) type 1a. More recently, ghrelin attracted enormous interest as new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also non-endocrine actions (e.g. cardiovascular activities) that are explained by the widespread distribution of ghrelin and GHS-R expression. The existence of GHS-R subtypes and evidence that neuroendocrine but not all other ghrelin actions are dependent on acylation in serine 3 add further complexity to the system whose major physiological role remains to be definitely clarified. What we are learning from the studies about the control of ghrelin secretion is that it is mostly under metabolic control; the most important impact of ghrelin would, in turn, be metabolic. However, a recent study states that the ghrelin knockout (KO) mouse is not anorectic dwarf and this evidence clearly depicts a remarkable difference from the leptin KO mouse. Nevertheless, the original and fascinating ghrelin story as well as its potential pathophysiological implications in endocrinology and internal medicine are not definitely canceled by this evidence. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, open questions that are waiting for an answer are: how many are the ghrelin receptors? Is ghrelin the or a GHS ligand, i.e. are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms that would play different actions? Within the next years these questions will find the appropriate answer and we'll know about the ghrelin system something more precise; this knowledge will more appropriately clarify the potential clinical perspectives.