Ghrelin Stimulates GH But Not Food Intake in Arcuate Nucleus Ablated Rats

Abstract

Ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHS-R(1a)), was originally purified from the rat stomach. Ghrelin mRNA and peptide have also been detected in the hypothalamus and pituitary. Ghrelin is a novel acylated peptide that regulates GH release and energy metabolism. GHS-R(1a) mRNA is expressed in the pituitary gland as well as in several areas of the brain including the hypothalamus. In this study, we examined whether ghrelin could stimulate GH secretion and feeding in chronic GHRH, neuropeptide Y, and agouti-related protein deficient rats that were neonatally treated with monosodium glutamate (MSG), which destroys the neurons in the hypothalamic arcuate nucleus (ARC). Intravenous (iv) administration of rat ghrelin (10 micro g/kg body weight) increased plasma GH levels significantly in the normal adult male rats during a GH trough period of pulsatile GH secretion, while iv injection of ghrelin in MSG-treated rats resulted in a markedly attenuated GH response. When rat ghrelin (10 micro g/rat) was administered intracerebroventricular (icv), plasma GH levels were increased comparably in normal control and MSG-treated rats. However, the GH release after icv injection of ghrelin was markedly diminished compared with that after iv administration of a small amount of ghrelin in normal control rats (icv: 10 micro g/rat, iv: approximately 4.0 micro g/rat), indicating that the GH-releasing activity of exogenous ghrelin is route dependent and at least in part via hypothalamic ARC. The icv administration of 1 micro g of ghrelin increased significantly 4-h food intake in normal control, whereas the peptide did not increase food intake in MSG-treated rats, indicating that the feeding response to ghrelin requires intact ARC. Taken together, the primary action of ghrelin on appetite control and GH releasing activity is via the ARC even though it might act on another type of GHS-R besides GHS-R(1a).

Appetite control

“…However, the orexigenic action of ghrelin is independent of its effects on GH (Tschop et al 2000, Shintani et al 2001, Tamura et al 2002. Ghrelin administration does not increase food intake in mice lacking GHS-R type 1a, suggesting that the orexigenic effects may be mediated by this receptor; however, these mice have normal appetite and body composition (Chen et al 2004a, Sun et al 2004.…”

“…c-Fos expression increases within ARC NPY-synthesizing neurons after peripheral administration of ghrelin (Wang et al 2002), and ghrelin fails to increase food intake following ablation of the ARC (Tamura et al 2002). Studies of knockout mice demonstrate that both NPY and AgRP signalling mediate the effect of ghrelin, although neither neuropeptide is obligatory (Chen et al 2004a).…”

Caudal brainstem delivery of ghrelin induces fos expression in the nucleus of the solitary tract, but not in the arcuate or paraventricular nuclei of the hypothalamus

“…The arcuate nucleus of the hypothalamus (Arc) is strongly implicated in the mediation of the hyperphagic response to ghrelin (Cowley et al, 2003;Currie et al, 2005;Hewson and Dickson, 2000;Olszewski et al, 2003a;Olszewski et al, 2003b;Ruter et al, 2003;Wren et al, 2000). Tamura et al, (2002), for example, showed that ablation of Arc neurons by neonatal MSG treatment eliminated the feeding response to lateral intracerebroventricular (i.c.v.) administration of ghrelin.…”

Ghrelin-induced GH secretion in domestic fowl in vivo and in vitro

“…While ghrelin may have pituitary sites of action in mammals, the in vivo GH responses to ghrelin in mammals is thought to be largely mediated through the central nervous system (CNS) (Date et al 2000, Wren et al 2000, Tamura et al 2002, Pinilla et al 2003. Indeed, ghrelin inhibits somatostatin (SRIF) release (Tolle et al 2001, Seoane et al 2003 and increases GHRH tone (Tannenbaum & Bowers 2001, Tannenbaum et al 2003, either of which would augment its pituitary action.…”

“…The in vivo potency of ghrelin in birds is thus unknown, as is its possible site of action. Although ghrelin directly stimulates GH release from mammalian pituitary cells (Kojima et al 1999, Yamazaki et al 2002, it also has hypothalamic sites of action (Date et al 2000, Tannenbaum & Bowers 2001, Tolle et al 2001, Tamura et al 2002, Wren et al 2002, Moreover, while pituitary sites of ghrelin action have been demonstrated, it is still uncertain if this is due to the direct stimulation of somatotrophs or the stimulation of other cell types that might indirectly regulate somatotroph function. Indeed, other secretagogues are thought to affect pituitary function by inducing paracrine cascades between heterologous cell types (e.g.…”