Exendin-4 Potently Decreases Ghrelin Levels in Fasting Rats

Abstract

Ghrelin is a potent orexigenic and adipogenic hormone that strongly influences fat deposition and the generation of hunger in obesity. Indeed, hyperghrelinemia appears to promote an increase in food intake as seen in Prader-Willi Syndrome (PWS). Exendin (Ex)-4 is an agonist of the glucagon-like peptide (GLP)-1 receptor (GLP-1r) that has anorexigenic and fat-reducing properties. Here, we report that Ex-4 reduces the levels of ghrelin by up to 74% in fasted rats. These effects are dose dependent and long lasting (up to 8 h), and they can be detected after both central and peripheral administration of Ex-4. Suppression of ghrelin was neither mimicked by GLP-1(7-36)-NH 2 nor blocked by the GLP-1r antagonist Ex-(9 -39). Moreover, it was independent of the levels of leptin and insulin. The decrease in ghrelin levels induced by Ex-4 may explain the reduced food intake in fasted rats, justifying the more potent anorexigenic effects of Ex-4 when compared with GLP-1. As well as the potential benefits of Ex-4 in type 2 diabetes, the potent effects of Ex-4 on ghrelin make it tempting to speculate that Ex-4 could offer a therapeutic option for PWS and other syndromes characterized by substantial amounts of circulating ghrelin. Diabetes 56: 143-151, 2007

Exendin-4 Improves Glycemic Control, Ameliorates Brain and Pancreatic Pathologies, and Extends Survival in a Mouse Model of Huntington's Disease

“…Plasma ghrelin levels were reduced in the Ex-4 -treated wild-type mice compared with the control wild-type mice (Fig. 3E), and this effect has also been observed in human subjects (33). The control Huntington's disease mice had significantly lower ghrelin levels compared with the wild-type mice, and Ex-4 treatment unexpectedly restored ghrelin levels in the Huntington's disease mice to that of wild-type mice (Fig.…”

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

“…Biologically, GLP-1 exerts a broad range of actions such as stimulating insulin release, reducing glucagon release, and reducing gastric emptying (Willms et al, 1996;Baggio et al, 2004), and at least some of its actions appear to be mediated through neuroendocrine mechanisms. CNS GLP-1 receptor activa-tion has been linked to the control of food intake (Tang-Christensen et al, 1996;Turton et al, 1996;Pérez-Tilve et al, 2007), some stress responses (Kinzig et al, 2003), glucose homeostasis (Sandoval, 2008), and locomotor activity (Knauf et al, 2008). However, a potential role of CNS GLP-1 receptor activity in the direct control of lipid deposition or lipid mobilization remains unknown.…”

Ghrelin and New Metabolic Frontiers

“…The GLP-1–induced suppression of ghrelin secretion might be involved in its anorexic effects. In addition, exendin-4 has been shown to decrease ghrelin levels in men [23]. It also stimulates exocrine pancreatic function, whereas ghrelin decreases it.…”