Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
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-...
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| Published in: | Diabetes (New York, N.Y.) Vol. 66; no. 4; pp. 1062 - 1073 |
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| Main Authors: | , , , , , , , , , , , , |
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| Language: | English |
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| ISSN: | 1939-327X |
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| 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-HT
) and 5-HT
serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT
, but surprisingly not the 5-HT
, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT
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. |
|---|---|
| AbstractList | 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-HT
) and 5-HT
serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT
, but surprisingly not the 5-HT
, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT
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. 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. |
| Author | Anderberg, Rozita H Richard, Jennifer E Reimann, Frank Wernstedt Asterholm, Ingrid Berqquist, Filip Skibicka, Karolina P López-Ferreras, Lorena Banke, Elin Eerola, Kim Lamy, Christophe M Gribble, Fiona M Hansson, Caroline Nissbrandt, Hans |
| Author_xml | – sequence: 1 givenname: Rozita H surname: Anderberg fullname: Anderberg, Rozita H organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 2 givenname: Jennifer E surname: Richard fullname: Richard, Jennifer E organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 3 givenname: Kim surname: Eerola fullname: Eerola, Kim organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 4 givenname: Lorena surname: López-Ferreras fullname: López-Ferreras, Lorena organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 5 givenname: Elin surname: Banke fullname: Banke, Elin organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 6 givenname: Caroline surname: Hansson fullname: Hansson, Caroline organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 7 givenname: Hans surname: Nissbrandt fullname: Nissbrandt, Hans organization: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 8 givenname: Filip surname: Berqquist fullname: Berqquist, Filip organization: Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 9 givenname: Fiona M surname: Gribble fullname: Gribble, Fiona M organization: MRC Metabolic Diseases Unit and Institute of Metabolic Science, University of Cambridge, Cambridge, U.K – sequence: 10 givenname: Frank surname: Reimann fullname: Reimann, Frank organization: MRC Metabolic Diseases Unit and Institute of Metabolic Science, University of Cambridge, Cambridge, U.K – sequence: 11 givenname: Ingrid surname: Wernstedt Asterholm fullname: Wernstedt Asterholm, Ingrid organization: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden – sequence: 12 givenname: Christophe M surname: Lamy fullname: Lamy, Christophe M organization: Laboratory of Neurometabolic Physiology, Department of Medicine, University of Fribourg, Fribourg, Switzerland – sequence: 13 givenname: Karolina P orcidid: 0000-0002-1430-0173 surname: Skibicka fullname: Skibicka, Karolina P email: karolina.skibicka@neuro.gu.se organization: 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 |
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| SubjectTerms | Aminopyridines - pharmacology Animals Anorexia Appetite - drug effects Body Weight - drug effects Dorsal Raphe Nucleus - metabolism Exenatide Feeding Behavior - drug effects Fenclonine - pharmacology Glucagon-Like Peptide 1 - pharmacology Glucagon-Like Peptide-1 Receptor - drug effects Glucagon-Like Peptide-1 Receptor - metabolism Hypoglycemic Agents - pharmacology Indoles - pharmacology Liraglutide - pharmacology Male Peptides - pharmacology Pyrrolidines - pharmacology Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT2A - drug effects Receptor, Serotonin, 5-HT2A - metabolism Receptor, Serotonin, 5-HT2C - drug effects Receptor, Serotonin, 5-HT2C - metabolism Serotonin - metabolism Serotonin Antagonists - pharmacology Venoms - pharmacology Weight Loss - drug effects |
| Title | Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight |
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