Biological Actions of Ghrelin
Ghrelin and Hypothalamus–Pituitary Endocrine Functions
GH-Releasing Activity. Ghrelin, as well as synthetic GHS, possesses a strong and dose-related GH-releasing effect (Kojima et al., 1999; Arvat et al., 2000, 2001; Peino et al., 2000; Seoane et al., 2000; Takaya et al., 2000; Wren et al., 2000; Broglio et al., 2003a). Ghrelin and GHRH have a synergistic effect indicating that they act, at least partially, via different mechanisms (Arvat et al., 2001; Hataya et al., 2001; Cunha & Mayo, 2002). Nevertheless, GH secretagogues need GHRH activity to fully elicit their GH-releasing effect and probably act by triggering GHRH-secreting neurones, being strongly inhibited by a GHRH antagonist as well as by a hypothalamus–pituitary disconnection (Pandya et al., 1998; Tannenbaum & Bowers, 2001; Popovic et al., 2003; Tannenbaum et al., 2003; Kamegai et al., 2004).
Ghrelin probably also acts as a functional somatostatin antagonist at both the pituitary and the hypothalamic level (Tannenbaum et al., 2003). In humans the GH response to ghrelin is partially refractory to exogenous somatostatin or cortistatin (Broglio et al., 2002a; Di Vito et al., 2002). The GH response to ghrelin and GHS is also partially refractory to other factors known to affect somatotroph secretion, such as glucose, lipids, arginine, cholinergic agonists and antagonists, IGF-I and GH itself (Broglio et al., 2002b,c; van der Lely et al., 2004). The GH-releasing action of ghrelin and GHS undergoes homologous desensitization under prolonged exposure to these molecules in both animals and humans (Micic et al., 2002; Orkin et al., 2003; Camina et al., 2004).
The GH-releasing effect of ghrelin and GHS is influenced by pharmacological doses of oestrogens; however, the somatotroph response to ghrelin administration is independent of gender while it undergoes marked age-related variations (Broglio et al., 2003a; van der Lely et al., 2004). As a reduced expression of the hypothalamic GHS receptors has been demonstrated in the aged human brain, an impairment of the ghrelin system could theoretically have a role in the age-related decrease of GH secretion (Muccioli et al., 1998; van der Lely et al., 2004).
Interestingly, the GH response to ghrelin has been reported to be clearly reduced not only in obesity, where it was expected due to the functional hyposomatotropism commonly present in this condition, but also in anorexia nervosa, a condition in which both spontaneous and GHRH-stimulated GH secretion have been reported to be increased (Tassone et al., 2003; Broglio et al., 2004a; varez-Castro et al., 2004). These findings suggest that in anorexia nervosa, chronic hyperghrelinaemia could induce some desensitization to exogenous ghrelin actions.
Ghrelin is likely to play a role in the GH response to fasting and energy restriction; the GH hyper- and hyposecretion that connote anorexia and obesity, respectively, could reflect the ghrelin hyper- and hyposecretion that have been demonstrated in these clinical conditions (Ariyasu et al., 2001; Tschop et al., 2001b; Shiiya et al., 2002). However, a feedback link between GH and ghrelin secretion has never been demonstrated and ghrelin does not play a role in mediating the GH response to the majority of pharmacological stimuli of somatotroph secretion such as insulin-induced hypoglycaemia, arginine, glucagon and cholinergic agonists (Lucidi et al., 2002; Broglio et al., 2004c,d).
PRL- and ACTH-releasing Activity. The stimulatory effect of ghrelin and GHS on PRL secretion in humans is slight, independent of both gender and age and probably involving both direct action on somatomammotroph cells and indirect hypothalamic actions (Arvat et al., 2001; Broglio et al., 2003a; Korbonits et al., 2004).
The acute stimulatory effect of ghrelin and GHS on the activity of the hypothalamic–pituitary (HPA) axis in humans is similar to that after naloxone, AVP and even corticotrophin-releasing hormone (CRH) but prolonged GHS administration apparently does not lead to an HPA axis hyperfunction (Korbonits et al., 2004; van der Lely et al., 2004). In physiological conditions, the ACTH-releasing activity of GHS depends totally on CNS-mediated mechanisms and probably involves CRH, AVP, neuropeptide Y (NPY) and Gamma-Aminobutyric Acid (GABA) neurones (Korbonits et al., 2004; van der Lely et al., 2004).
The ACTH response to GHS is generally sensitive to the negative feedback control by cortisol (van der Lely et al., 2004). However, the stimulatory effect of ghrelin and GHS on corticotroph secretion is surprisingly enhanced and higher than that of hCRH in patients with pituitary ACTH-dependent Cushing's disease, probably reflecting an action on the pituitary tumoral corticotroph cells where both ghrelin and GHS-R are expressed (Leal-Cerro et al., 2002). Ghrelin and GHS-R expression have also been shown in some ectopic ACTH-releasing tumours and, accordingly, enhanced ACTH and cortisol responses to ghrelin has been reported in some patients with ectopic Cushing's syndrome (Korbonits et al., 2001a, 2004; Leal-Cerro et al., 2002).
Influence on Gonadotroph Secretion. Intracerebroventricular injection of ghrelin has been reported to be able to decrease the frequency of pulsatile LH secretion leading to a decrease in LH concentration (Furuta et al., 2001; Fernandez-Fernandez et al., 2004). These findings probably reflect a modulation of the activity of the GnRH pulse generator and indicate that ghrelin also plays a role in the central control of gonadotroph function (Furuta et al., 2001). Overall, this neuroendocrine action of ghrelin would fit well with the hypothesis that ghrelin, in collaboration with leptin, plays a role in the prompt turn-off of the gonadal axis that, coupled with the amplification of somatotroph and corticotroph functions, occurs during starvation. Ghrelin could, however, also play a role in the control of the gonadal axis at the peripheral level (see below). Printer- Friendly Email This