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Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight

Journal article
Authors Rozita H Anderberg
Jennifer E. Richard
Kim Eerola
Lorena López-Ferreras
Elin Banke
Caroline Hansson
Hans Nissbrandt
Filip Bergquist
F. M. Gribble
F. Reimann
Ingrid Wernstedt Asterholm
C. M. Lamy
Karolina P Skibicka
Published in Diabetes
Volume 66
Issue 4
Pages 1062-1073
ISSN 0012-1797
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Neuroscience and Physiology, Department of Pharmacology
Pages 1062-1073
Language en
Links dx.doi.org/10.2337/db16-0755
Keywords Aminopyridines/pharmacology, Animals, Anorexia, Appetite/*drug effects, Body Weight/*drug effects, Dorsal Raphe Nucleus/*metabolism, Feeding Behavior/drug effects, Fenclonine/pharmacology, Glucagon-Like Peptide 1/*pharmacology, Glucagon-Like Peptide-1 Receptor/*drug effects/metabolism, Hypoglycemic Agents/*pharmacology, Indoles/pharmacology, Liraglutide/pharmacology, Male, Peptides/pharmacology, Pyrrolidines/pharmacology, Rats, Rats, Sprague-Dawley, Receptor, Serotonin, 5-HT2A/*drug effects/metabolism, Receptor, Serotonin, 5-HT2C/*drug effects/metabolism, Serotonin/*metabolism, Serotonin Antagonists/pharmacology, Venoms/pharmacology, Weight Loss/drug effects
Subject categories Neuroscience

Abstract

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.

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