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.
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.