Effects of glucagon-like peptide 1 and oxyntomodulin on neuronal activity of ghrelin-sensitive neurons in the hypothalamic arcuate nucleus

Abstract

Glucagon-like peptide 1 (GLP-1) and oxyntomodulin (OXM) are structurally related gastrointestinal hormones that are secreted in response to food intake. They reduce food intake and body weight and exert partly overlapping actions on glucose homeostasis and gastrointestinal function. The hypothalamic arcuate (ARC) nucleus is among the central structures expressing a high density of GLP-1 receptors (GLP-1R), which are known to be activated by both peptides. It was the aim of our electrophysiological studies to characterize the effects of GLP-1 and OXM on functionally defined ghrelin-sensitive ARC neurons. GLP-1 and OXM (10(-7) M) exerted excitatory effects in about two-thirds of ghrelin-inhibited neurons and in approximately one-third of ghrelin-excited cells. In addition, a minor fraction of the ghrelin-excited cells was inhibited by both peptides. There was a high degree of cosensitivity to GLP-1 and OXM, and the effects of both hormones were blocked by the GLP-1R antagonist exendin(9-39). The GLP-1R-mediated excitations and inhibitions persisted under synaptic blockade, indicating a direct postsynaptic mode of action. Our results demonstrate that GLP-1 and OXM directly and similarly alter neuronal activity in the ARC, probably via a common GLP-1R-mediated mechanism. Ghrelin-antagonistic effects on neuronal activity, which might be implicated in ghrelin-antagonistic in vivo actions, resulting from GLP-1R stimulation (e.g., GLP-1R dependent supression of food intake), predominated in ghrelin-inhibited ARC neurons. However, a subset of ghrelin-excited ARC neurons showed responses to OXM or GLP-1, suggesting the existence of a common mode of action for these hormones; the functional relevance of this effect remains to be elucidated.