title: Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.
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-HT2Cserotonin 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-HT2Areceptors 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.
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Rozita H
authors.initials: RH
authors.lastname: Anderberg
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Richard
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kim
authors.initials: K
authors.lastname: Eerola
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lorena
authors.initials: L
authors.lastname: López-Ferreras
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Elin
authors.initials: E
authors.lastname: Banke
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hansson
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Nissbrandt
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Berqquist
authors.affiliation: MRC Metabolic Diseases Unit and Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: MRC Metabolic Diseases Unit and Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wernstedt Asterholm
authors.affiliation: Laboratory of Neurometabolic Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Lamy
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden karolina.skibicka@neuro.gu.se.
authors.forename: Karolina P
authors.identifier: 0000-0002-1430-0173
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000855:Anorexia; D001066:Appetite / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D000077270:Exenatide; D005247:Feeding Behavior / Q000187:drug effects; D010134:Fenclonine / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D010455:Peptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014688:Venoms / Q000494:pharmacology; D015431:Weight Loss / Q000187:drug effects
chemical_list: C476157:(2R,4R)-4-hydroxy-2-(2-(2-(2-(3-methoxy)phenyl)ethyl)phenoxy)ethyl-1-methylpyrrolidine hydrochloride; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007211:Indoles; D010455:Peptides; D011759:Pyrrolidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D014688:Venoms; D012701:Serotonin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D010134:Fenclonine