Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice

Abstract

Obestatin is a recently discovered peptide hormone that appears to be involved in reducing food intake, gut motility and body weight. Obestatin is a product of the preproghrelin gene and appears to oppose several physiological actions of ghrelin. This study investigated the acute effects of obestatin (1–23) and the truncated form, obestatin (11–23), on feeding activity, glucose homeostasis or insulin secretion. Mice received either intraperitoneal obestatin (1–23) or (11–23) (1 μmol/kg) 4 h prior to an allowed 15 min period of feeding. Glucose excursions and insulin responses were lowered by 64–77% and 39–41%, respectively, compared with saline controls. However this was accompanied by 43% and 53% reductions in food intake, respectively. The effects of obestatin peptides were examined under either basal or glucose (18 mmol/kg) challenge conditions to establish whether effects were independent of changes in feeding. No alterations in plasma glucose or insulin responses were observed. In addition, obestatin peptides had no effect on insulin sensitivity as revealed by hypoglycaemic response when co-administered with insulin. Our observations support a role for obestatin in regulating metabolism through changes of appetite, but indicate no direct actions on glucose homeostasis or insulin secretion.

Introduction

Obestatin is a 23 amino acid peptide produced in the stomach that appears to be involved in the regulation of energy balance [35]. Obestatin is transcribed on the preproghrelin gene and C-terminal amidation is a prerequisite for biological activity [35]. Several of the actions of obestatin appear to oppose the actions of ghrelin [29], [31]. Most notably, obestatin appears to be a potent appetite-suppressant causing reductions in food intake, body weight and jejunal contraction in rodents [35]. Contrastingly, ghrelin has positive effects on energy balance stimulating food intake, gastric acid secretion, gastrointestinal motility and increasing feelings of hunger in humans [15], [21], [26], [27], [32], [33]. Also, recent information indicates that obestatin reduces fluid intake by altering of thirst mechanisms within the brain [24].

Ghrelin appears to be involved in regulating several important endocrine systems. It stimulates the release of growth hormone, lactotrophs and corticotrophs; inhibits somatostatin secretion from the endocrine pancreas and regulates gonadal function [4], [13], [27], [30]. Of particular note are recent observations that ghrelin may regulate glucose homeostasis and insulin secretion. Ghrelin has been shown to reduce insulin secretion in isolated rat pancreas [13], although this has not yet been confirmed [10]. Recent investigations have found that administration of ghrelin to humans lowers insulin secretion and increases plasma glucose [3], [4], [6], [7], but this also remains controversial [1], [2].

The G-protein coupled receptor, GPR39, has been proposed to be the target receptor of obestatin [35]. This has not been confirmed by other studies [18], [20]. This receptor is present in many regions of the brain including the pituitary gland, hypothalamus and cerebral cortex [35]. However, this conflicts with recent evidence of the absences of both GPR39 in the hypothalamus [19] and obestatin in the brain [23]. More puzzlingly, it would appear that obestatin is not transported across the blood–brain barrier [23]. GPR39 appears to be strongly expressed in the jejunum, duodenum, stomach, ileum and liver, but has also been found to a lesser extent in the pancreas [35]. Although the presence of GPR39 in pancreatic tissue has not been confirmed by others [19], significant levels of obestatin immunoreactivity were recently reported in perinatal rat pancreas [9]. Furthermore, obestatin immunoreactivity positively correlated with insulin concentrations, and since acylated ghrelin which is also found in the pancreas inhibits insulin secretion, it has been suggested that obestatin may potentiate insulin release [9]. The recent discovery of obestatin in 2005, means that many of its biological actions remain to be identified, including whether this peptide influences in vivo glucose homeostasis or insulin secretion. Since ghrelin raises blood glucose and lowers insulin secretion, we sought to investigate whether obestatin administration might exert opposite effects on glucose homeostasis and insulin secretion. We investigated the metabolic effects of obestatin after feeding, under basal conditions, or following intraperitoneal glucose. Furthermore, we assessed whether obestatin could augment insulin action by evaluating the hypoglycaemic response to insulin.