GHRANS · Ghrelin regulation by the autonomus nervous system
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-10-01 → 2005-09-30
- EU contribution
- €37,711
- Participants
- 1
- Scheme
- ERG
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Results in brief
Final Activity Report Summary - GHRANS (Ghrelin regulation by the autonomous nervous system)
The aim of this study was to investigate the regulation of ghrelin, a potent orexigenic peptide and modulator of energy metabolism, by the Autonomous nervous system (ANS), and the identification of whether the ANS mediated the effects of the analogue of Glucagon-like peptide-1 (GLP-1), exendin-4, on ghrelin levels. In order to asses this question we used several manipulations of the ANS activity, either pharmacological or surgical, in rats with restricted access to food or 'ad libitum' fed. We also tested these manipulations in two different models of experimental diabetes, namely the MKR mice, which served as a model for type II diabetes, and the Streptozotocin (STZ)-treated rats, which were used as a model for type I diabetes. Moreover, we recently reported that Ex-4, a potent agonist of the GLP-1 receptor, was capable of potently reducing the circulating ghrelin levels in fasting rats. The effects of Ex-4 on ghrelin levels were dose-dependent, time-dependent and long-lasting. In this project, we stated for the first time that the activity of the parasympathetic branch of ANS was very relevant in the control of the physiological variations of ghrelin levels in fasting or feeding rats. Ex-4 was able to activate the sympathetic branch of the ANS; however, the variations in the activity of the ANS had no influence on ghrelin responses to Ex-4. Ex-4 was the first drug that was reported to be able to potently decrease ghrelin levels and the unique factor able to do so regardless food intake. As we demonstrated, its effects on ghrelin were independent of its capacity to increase insulin secretion or variations in glucose levels. Furthermore, Ex-4 was recently approved for the treatment of type II diabetes mellitus. Our results suggested that Ex-4 could offer, for the first time, a therapeutic tool to treat hyperghrelinemic pathological situations, such as the ones occurring in Prader-Willi syndrome, a genetic form of morbid obesity with low life expectancy and no other treatment apart from bariatric surgery. Ex-4 could therefore be a pharmacologic alternative. Ex-4 could also be useful in other common metabolic diseases, such as obesity, cachexia and anorexia nervosa.
Data: CORDIS, © European Union
Project objective
Ghrelin is a gastric peptide with potent or exigenic effects, which has been related to diabetic hyperphagia. Previous data showed that Exendine-4 (Ex-4), a long-lasting action GLP-1 agonist, which resist DPP-IV enzymatic degradation, stimulated insulin secretion, reduces food intake and also reduces blood circulating Ghrelin levels in fasting rats. Some of the effect of EX4 are known o be mediated by changes in the activity of the autonomous nervous system (ANS). EX4 is postulated to have potential therapeutic effects in type II diabetes mellitus.Specific scientific objectives:1. To study whether the autonomous nervous system is able to regulate the Ghrelin levels in the rat in ad libitum food intake diet. And to study if the autonomous nervous system activity interferes within the inhibitory effects of Exendin-4 upon Ghrelin levels in the fasting rat, both in normal and diabetics.2. To study whether Exendin-4 reduces Ghrelin levels in the MKR transgenic mouse, as an optimal model for type II diabetes, and how it could influence diabetic hyperphagia.3. To study whether Exendin-4 reduces mRNA Ghrelin levels in the stomach in normal rats and in two models of experimental diabetes STZ-treated rats (DM-1) and MKR mice (DM-2).The inhibitory effect of Ex-4 upon Ghrelin levels, last during four hours, at least, making sense not only affect its secretion by also its production in the stomach, reason by, we propose to evaluate Ghrelin mRNA levels in response to Ex-4 in gastric tissue.
Original text from CORDIS.
Participants
- UNIVERSIDAD DE VIGO · VIGOCoordinatorSpain
Links
Data: CORDIS, © European Union