Bolus administration of obestatin does not change glucose and insulin levels neither in the systemic nor in the portal circulation of the rat
Introduction
Ghrelin, a 28 amino acid peptide produced mainly by the stomach, was originally discovered as a natural ligand of the Growth Hormone Secretagogue Receptor type 1a (GHS-R1a) [15]. Despite being primarily identified as a potent GH stimulating factor, ghrelin has been demonstrated to have a wide spectrum of biological activities, such as stimulation of prolactin and ACTH secretion, promotion of gastric motility and acid secretion, and modulation of cardiovascular function [23], [25]. One of its most intriguing functions is the long-term and short-term regulation of energy balance. Continuous administration of ghrelin to rodents induces increased food intake resulting in weight gain, whereas in humans 24-h plasma profiles show marked preprandial increases and postprandial decreases in circulating ghrelin concentrations, which suggests an orexigenic effect [5], [24], [27].
Ghrelin is derived from a 117 amino acid peptide called preproghrelin, which is predominantly produced in X/A like cells in the stomach [15]. In 2005, Zhang et al. identified a second peptide encoded by the GHRL gene, using comparative genomic analysis, and called it obestatin [30]. This amidated 23 amino acid peptide and ghrelin appeared to be differentially secreted since fasting and subsequent refeeding in rats induced a rise and subsequent fall in ghrelin concentrations, whereas no changes in obestatin concentrations were observed [30]. Additionally, acute intraperitoneal and intracerebroventricular administration of obestatin suppressed food intake, while daily administration of obestatin suppressed body weight gain and induced delayed gastric emptying [30]. These results suggested that obestatin and ghrelin had opposing effects on food intake and body weight regulation.
Following these initial results, obestatin has been the topic of an ongoing discussion. Many studies failed to reproduce the inhibiting effect on food intake and body weight gain or questioned its role in energy homeostasis [6], [10], [18], [22], [28], [31]. Additionally, the hypothesis that obestatin exerted its effect by stimulating the orphan receptor GPR39, was rejected by several groups including the original authors [4], [13], [17], [29]. On the other hand, several studies in rodents confirmed an anorexigenic effect of obestatin, either endogenous or by counteracting the orexigenic effect of ghrelin [12], [16].
Acylated ghrelin is known to induce insulin resistance [2], [7], [26]. Therefore, it could be hypothesized that obestatin does affect insulin and glucose secretion as well. Recently, two studies have evaluated glucose and insulin responses to obestatin administration, both measuring concentrations in the systemic circulation [12], [20]. However, a problem that may be encountered in evaluating the effect of obestatin on glucose and insulin metabolism is its short half-life [19]. Obestatin is mainly produced in the stomach and might accordingly exert its effect primarily in the portal system [30]. Therefore, measurements of systemic insulin and glucose concentrations may fail to demonstrate this effect. Additionally, hepatic effects of obestatin may be overlooked when measuring systemic concentrations of glucose and insulin only.
In the present study, we used a previously validated rat model, which allowed us to simultaneously measure systemic and portal insulin and glucose concentrations [8], [9], [30]. The aim of this study was to evaluate acute effects of intravenous administration of obestatin on glucose and insulin metabolism in fasted and glucose-stimulated conditions.
Section snippets
Animals
Male Wistar rats (age: 10–12 weeks; weight: 350–400 g, Harlan Netherlands BV, Horst, The Netherlands) were housed in groups in a temperature-controlled room under a 12-h light/12-h dark cycle, and maintained on pelleted chow with free access to water. The animals were housed for at least 1 week before starting the experiments, in order to allow acclimatization. Animal protocols were in compliance with the Dutch regulations on animal welfare and approved by the institutional Animal Welfare
Baseline glucose and insulin levels
Baseline insulin concentrations in the portal circulation were approximately 2.5 times higher than in the systemic circulation (portal 4.47 ± 0.46 μg/l vs. systemic 1.7 ± 0.22 μg/l), while the difference in baseline portal and systemic glucose levels was small (portal 6.78 ± 0.51 mmol/l vs. systemic 8.25 ± 0.59 mmol/l). Both baseline glucose (portal 7.79 ± 0.65 mmol/l, systemic 9.96 ± 0.65 mmol/l) and insulin (portal 4.75 ± 0.60 μg/l, systemic 1.77 ± 0.24 μg/l) levels were higher in the control groups (IVGTT and
Discussion
In the present study we demonstrated that acute intravenous administration of obestatin does not change glucose and insulin concentrations in the systemic circulation. This lack of effect was observed in fasted as well as in glucose-stimulated conditions. There was only a slight difference in peak glucose concentrations after IVGTT, but it can be debated whether this has any clinical relevance. Additionally, we measured glucose and insulin directly in the portal vein. These results, however,
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Cited by (0)
- 1
Department of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology, University of Turin, via P. Giuria 13, 10125 Turin, Italy.
- 2
Equally participated in the study.