Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin

Abstract

Background. Proghrelin, produced by the ghrelin (A-like) cells of the gastric mucosa, gives rise to cleavage products, including desacyl ghrelin, acyl ghrelin and obestatin. The products are thought to be secreted concomitantly. In an earlier study we found acyl ghrelin and obestatin, but not desacyl ghrelin, to suppress the release of hormones from isolated islets of mouse and rat pancreas.Results. Using isolated mouse pancreatic islets to study the suppression of the spontaneous secretion of pancreatic polypeptide (PP) by acyl ghrelin and obestatin, we determined the EC 50 values for the two peptides. For acyl ghrelin it was 2 x 10 -13 M (ranging from 1.7 to 2.8 x 10 -13 M), for obestatin it was 10 -13 M (ranging from 0.3 to 1.1 x 10 -13 M). The Hill coefficient (i.e. the midpoint slope) for the acyl ghrelin dose-response curve was 0.30 (ranging from 0.21 to 0.35); the corresponding value for obestatin was 0.35 (ranging from 0.21 to 0.35). The PP-releasing effect of acyl ghrelin, but not that of obestatin, was counteracted by desacyl ghrelin. The acyl ghrelin dose-response curve was shifted to the right in a parallel manner by increasing concentrations of desacyl ghrelin. A Schild plot was constructed with a slope of 0.78, giving an apparent pA 2 value of 14.Conclusions. The results favour the view that acyl ghrelin and obestatin suppress spontaneous PP secretion at physiologically relevant concentrations and that they act on separate receptors. However, we conclude also that desacyl ghrelin acts as a competitive, surmountable (and quite potent) inhibitor of acyl ghrelin. In view of the allegedly high circulating concentrations of desacyl ghrelin it is to be expected that the effect of acyl ghrelin -but not that of obestatin -will be impaired, in fact probably severely blunted by desacyl ghrelin, thereby compromising the functional significance of circulating acyl ghrelin. In addition, we suggest that isolated pancreatic islets are well suited for studies of receptors to acyl ghrelin and obestatin, and that suppression of PP secretion represents a convenient way to measure the effect of both these peptides.

MECHANISMS IN ENDOCRINOLOGY: Ghrelin: the differences between acyl- and des-acyl ghrelin

“…These results suggest that DAG suppresses AG-induced food intake by preventing the increase in neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons (17). Kumar et al also reported the antagonistic properties of DAG on AG (19).…”

“…Trophic and protective effects on β-cells in humans and rodents (16,21,55) Inhibition of ghrelin in humans and rodents (17,19) Restoration of EPC/CAC number and function in DM patients and rodents (40) Muscle regeneration in rodents (27,39) Des-acyl ghrelin (glucose) in humans and rodents (34,54) Figure 1 Overview of des-acyl ghrelin actions, along with some references for further reading.…”

“…relevant concentrations by acting through separate receptors (19). Gauna et al (20) reported that administration of AG in humans reduces insulin sensitivity, whereas the combination of AG plus DAG strongly improves insulin sensitivity.…”

Abdominal surgery inhibits circulating acyl ghrelin and ghrelin-O-acyltransferase levels in rats: role of the somatostatin receptor subtype 2

“…Only acyl ghrelin binds to the growth hormone secretagogue receptor (GHS-R) 1a (7) [since then renamed ghrelin (GRLN) receptor (17)] to induce a GRLN receptor-dependent stimulation of gastric motility (21) and food intake (70) whereas desacyl ghrelin's actions are exerted independently of the GRLN receptor (60). Recent evidence indicates that coadministration of desacyl ghrelin counteracts the stimulatory effect of intrathecal injection of ghrelin on propulsive contraction of the rat colon (28), the orexigenic action of intraperitoneal injection of acyl ghrelin in rats (32), and the stimulation of pancreatic polypeptide (PP) secretion in isolated mouse islets (36) suggestive of a negative interaction between both peptides, although the physiological role of desacyl ghrelin is still to be established (33,60).…”

Stomach - Key Player in the Regulation of Metabolism

“…An increasing number of studies suggest that desacyl ghrelin can act as a potent functional inhibitor of ghrelin [83]. It seems to antagonize ghrelin's effects on several functions including food intake [84,85]. Moreover, desacyl ghrelin can improve postprandial glycemia, especially in those subjects in whom preprandial acylated ghrelin levels are high.…”