Integrating GHS into the Ghrelin System

Abstract

Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development.

Figure 1

Principal peptide products of preproghrelin (a) and primary actions of ghrelin recognized to date (b) (unpublished line drawing).

Figure 2

Model-based functional networks subserving GH secretion, showing major effects of GH-releasing hormone (GHRH) and somatostatin (SS) as modified by GHS (ghrelin). D ₁ and D ₂ denote time delays. ArC and PeV define arcuate and periventricular nuclei (adapted from [41]).

Figure 3

Key hormonal, gastrointestinal, nutritional, stress-related, infectious, and physiological regulators of gastric ghrelin secretion inferred in mammalian species.

Figure 4

Strong impact of bolus ghrelin dose and ghrelin isotype (acylated [bioactive] or total ghrelin) on the metabolic clearance rate (MCR) of ghrelin in postmenopausal women. Means with different superscripts differ significantly by post hoc analysis after ANOVA (P = .003) (a). Linear relationship of steady-state MCR of acylated ghrelin to plasma acylghrelin concentration during constant ghrelin infusion (b). Adapted from [91] with permission.

Figure 5

Basic ghrelin network influencing locomotion (left upper quadrant), gastrointestinal signals to appetitive and anorexigenic centers (middle section), gastric motility (right upper quadrant) or peripheral target tissues (right lower segment). Unpublished schema.

Figure 6

Complementarity of ghrelin's vagal-nerve signaling via GHS-R1a with that of other orexigenic (left) or anorexigenic (right) peptides. PYY: polypeptide YY; GLP-1: glucagon-like peptide. Unpublished sketch.

Figure 7

Lifetime variations in GHS (hexarelin) action to induce GH secretion in prepubertal, pubertal, adult, and aged humans (redrawn with permission from [488]).

Figure 8

Continuous subcutaneous (SC) infusion of saline, GHRH or ghrelin, or both (1 μg/kg/hour) for 24 hours in a normal 69-year-old woman. Data are 20-minutes GH concentrations (y-axis) plotted against time (x-axis). AUC: area under the GH versus time curve. IGF-I concentrations at the start and end of each infusion are stated in the upper-right corner of each panel in units of μg/L.