Glucagon-Like Peptide 1 Excites Hypocretin/Orexin Neurons by Direct and Indirect Mechanisms: Implications for Viscera-Mediated Arousal

Glucagon-like peptide-1 (GLP-1) increases pancreatic insulin secretion via a direct action on pancreatic beta-cells. A high density of GLP-1-containing neurons and receptors is also present in brain stem vagal circuits; therefore, the aims of the present study were to investigate 1) whether identified pancreas-projecting neurons of the dorsal motor nucleus of the vagus (DMV) respond to exogenously applied GLP-1, 2) the mechanism(s) of action of GLP-1, and 3) whether the GLP-1-responsive neurons (putative modulators of endocrine secretion) could be distinguished from DMV neurons responsive to peptides that modulate pancreatic exocrine secretion, specifically pancreatic polypeptide (PP). Whole cell recordings were made from identified pancreas-projecting DMV neurons. Perfusion with GLP-1 induced a concentration-dependent depolarization in approximately 50% of pancreas-projecting DMV neurons. The GLP-1 effects were mimicked by exendin-4 and antagonized by exendin-(9-39). In approximately 60% of the responsive neurons, the GLP-1-induced depolarization was reduced by tetrodotoxin (1 microM), suggesting both pre- and postsynaptic sites of action. Indeed, the GLP-1 effects were mediated by actions on potassium currents, GABA-induced currents, or both. Importantly, neurons excited by GLP-1 were unresponsive to PP and vice versa. These data indicate that 1) GLP-1 may act on DMV neurons to control pancreatic endocrine secretion, 2) the effects of GLP-1 on pancreas-projecting DMV neurons are mediated both via a direct excitation of their membrane as well as via an effect on local circuits, and 3) the GLP-1-responsive neurons (i.e., putative endocrine secretion-controlling neurons) could be distinguished from neurons responsive to PP (i.e., putative exocrine secretion-controlling neurons).

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“…16, 32, and 35). The effects of GLP-1 on neuronal populations have, however, received scant attention (1,27).…”

Section: Discussionmentioning

confidence: 99%

Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons

Wan

Coleman

Travagli³

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The actions of GLP-1 on VMH and LH contribute to feeding termination and satiety [35][36][37]. Orexigenic and anorexigenic peptides located in the VMH, LH, paraventricular, and arcuate nuclei interact with one another in such a way that they can induce a characteristic feeding behavior.…”

Section: Discussionmentioning

confidence: 99%

Leptin but not neuropeptide Y up-regulated glucagon-like peptide 1 receptor expression in GT1-7 cells and rat hypothalamic slices

et al. 2008

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“…GLP-1 also stimulates the electrical activity of orexin/hypocretin neurons (Acuna-Goycolea and van den Pol, 2004), in which, in contrast to POMC neurons, it reduces Ca 2ϩ currents and activates a nonselective cationic current. This implies that different signaling pathways exist in these two cell types.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide 1 Stimulates Hypothalamic Proopiomelanocortin Neurons

Ma¹,

Ashcroft²

2007

J. Neurosci.

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Glucagon-Like Peptide 1 Excites Hypocretin/Orexin Neurons by Direct and Indirect Mechanisms: Implications for Viscera-Mediated Arousal

Cited by 112 publications

References 79 publications

Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons

Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons

Leptin but not neuropeptide Y up-regulated glucagon-like peptide 1 receptor expression in GT1-7 cells and rat hypothalamic slices

Glucagon-Like Peptide 1 Stimulates Hypothalamic Proopiomelanocortin Neurons

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