Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin: A study of pancreatic polypeptide secretion from mouse islets

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 × 10 − 13 M (ranging from 1.7 to 2.8 × 10 − 13 M), for obestatin it was 10 − 13 M (ranging from 0.3 to 1.1 × 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.