Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion

Abstract

(GHS) receptor that stimulates pulsatile GH secretion markedly. At present, no formal construct exists to unify ensemble effects of ghrelin, GH-releasing hormone (GHRH), somatostatin (SRIF), and GH feedback. To model such interactions, we have assumed that ghrelin can stimulate pituitary GH secretion directly, antagonize inhibition of pituitary GH release by SRIF, oppose suppression of GHRH neurons in the arcuate nucleus (ArC) by SRIF, and induce GHRH secretion from ArC. The dynamics of such connectivity yield self-renewable GH pulse patterns mirroring those in the adult male and female rat and explicate the following key experimental observations. 1) Constant GHS infusion stimulates pulsatile GH secretion. 2) GHS and GHRH display synergy in vivo. 3) A systemic pulse of GHS stimulates GH secretion in the female rat at any time and in the male more during a spontaneous peak than during a trough. 4) Transgenetic silencing of the neuronal GHS receptor blunts GH pulses in the female. 5) Intracerebroventricular administration of GHS induces GH secretion. The minimal construct of GHS-GHRH-SRIF-GH interactions should aid in integrating physiological data, testing regulatory hypotheses, and forecasting innovative experiments. somatotropic axis; growth hormone secretagogues; feedback; mathematical model; hormone pulsatility; hypothalamus; pituitary GHRELIN AND SYNTHETIC GROWTH HORMONE SECRETAGOGUES (GHS) stimulate pulsatile growth hormone (GH) secretion via combined hypothalamohypophyseal mechanisms. The GHS receptor is expressed by somatotrope cells and arcuate nucleus (ArC) neurons containing GHRH and other peptides (40,44). Ghrelin and GHS act directly on GH-secreting (somatotrope) cells and indirectly on the inhibitory signal somatostatin (SRIF) and the peptidyl agonist GH-releasing hormone (GHRH) (13,27,44,51). In particular, GHS stimulate somatotropes in vitro but are synergistic with GHRH, induce ArC GHRH release, and antagonize certain hypothalamic actions of SRIF in vivo (3,10,13,27,37,40,51). GHRH potentiates feedforward drive by GHS because passive immunoneutralization or pharmacological antagonism of GHRH and truncational mutation of the GHRH receptor attenuate GHS-evoked GH secretion markedly in the rat, mouse, and human (31,35,63,65,68,78). In contradistinction, GHS and GHRH do not synergize in vitro (70, 89). Pituitary portal vein sampling studies have indicated that GHS infusion elicits ArC GHRH release in the conscious sheep (31, 35). Other experiments have established that GHS can oppose inhibition by SRIF and octreotide in the anterior pituitary gland and the hypothalamus (25)(26)(27)71). No formalism incorporates these multilocus actions of GHS into available constructs of self-renewable GH pulses mediated by GHRH-SRIF-GH feedback interactions (34,53,61,72).Current models of the basic properties of the GH pulse renewal process assume reciprocal interactions among GHRH, SRIF,. In the present work, we have used this foundation in an effort to incorporate the known effects of GHS in a simple network-l...

Interactions of ghrelin signaling pathways with the GH neuroendocrine axis: a new and experimentally tested model

“…Thus, compared with a previously suggested model (Farhy & Veldhuis 2005), the major novel features of the present model are a) the role played by NPY, a powerful orexigenic hormone, which also stimulates the release of SRIF (Rettori et al 1990), and b) the dissimilar functions of ghrelin in the hypothalamus and in the pituitary. Furthermore, the predictions of this model were experimentally tested and confirmed in the present report.…”

Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation

“…In animal models, the increase in GH leads to prompt somatostatin release, which inhibits GHRH and sensitizes the somatotrope to the next GHRH stimulus. In this perspective, ghrelin further amplifies GH release (26).…”

Determinants of GH-releasing hormone and GH-releasing peptide synergy in men

“…A few studies have used simultaneous GHRH and GHRP infusions to evaluate GH reserve in potentially hypopituitary patients (4,24,36,38). Transgenic, biomathematical, pharmacological, electrophysiological, and clinical models establish that GHRH and ghrelin/GHRP stimulate GH secretion synergistically (13,16,28,34,40). However, very little is known about the physiological factors that modulate GHRH-GHRP synergy in healthy individuals (36,38).…”