Endocrine Abstracts (2006) 11 S2

A tale of modern endocrinology

Felipe Casanueva



Growth hormone (GH) is regulated by two antagonistic hypothalamic hormones, GHRH and somatostatin, plus the liver-derived hormone IGF-I and metabolic signals. Then GH actions are implicated on somatic growth and in the regulation of general metabolism.

Developed in the seventies of past century, GH secretagogues (GHS) are small artificial molecules, either peptidyl or non-peptidyl, who actively discharge GH in all animal species so far studied and through any route of administration. No similar compounds exist in nature as they were formulated through an iterative process of trial and modification based on its capability to release GH in vitro. Curiously, these invented compounds were instrumental for the cloning of the GHS receptor (GHS-R).

Using this peculiar ‘orphan receptor’, ghrelin was isolated from the gastrointestinal area. Ghrelin activation of its cognate receptor leads to three main type of actions: 1) GH secretion, 2) appetite and energy metabolism regulation, and 3) other CNS actions like regulation of sleep and anxiety. The development of ghrelin antagonists allowed a better understanding of the physiological role of this new hormone, suggesting that the receptor mediating the release of GH is different or that there are different subtypes from those regulating appetite and metabolism. On the other hand, the GHS-R manifests a peculiar pattern of internalization and a cross-talk with other intracellular signalling systems, such as adenosine and GHRH receptors.

Ghrelin anticipates the initiation of meals and releases GH. In catabolic situations, raised ghrelin may induce enhanced food intake, increased gastric emptying and food assimilation, coupled with GH levels which would promote a prompt nutrient incorporation to muscles and to fat reserves.

It is customary that after discovering a new hormone, the following step is the cloning of the cognate receptor and finally the development of analogues for further clinical use. In the history of ghrelin, a ‘reverse pharmacology’ process was used as the GHS can be considered bona fide analogues of ghrelin, generated decades before the natural compound. With the coming in scene of obestatin, a ghrelin-gene derived peptide, the fascinating interplay of several hormones regulating GH secretion and energy homeostasis may start to be unravelled.

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