Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

Giuseppe D'Agostino; David Lyons; Claudia Cristiano; Miriam Lettieri; Cristian Olarte-Sanchez; Luke K Burke; Megan Greenwald-Yarnell; Celine Cansell; Barbora Doslikova; Teodora Georgescu; Pablo Blanco Martinez de Morentin; Martin G Myers; Justin J Rochford; Lora K Heisler

doi:10.1016/j.cmet.2018.07.017

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

Giuseppe D'Agostino, David Lyons, Claudia Cristiano, Miriam Lettieri, Cristian Olarte-Sanchez, Luke K Burke, Megan Greenwald-Yarnell, Celine Cansell, Barbora Doslikova, Teodora Georgescu, Pablo Blanco Martinez de Morentin, Martin G Myers, Justin J Rochford, Lora K Heisler

Research output: Contribution to journal › Article › peer-review

Abstract

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.

Original language	English
Pages (from-to)	619-630.e5
Journal	Cell Metabolism
Volume	28
Issue number	4
Early online date	23 Aug 2018
DOIs	https://doi.org/10.1016/j.cmet.2018.07.017 https://doi.org/10.1016/j.cmet.2018.07.017
Publication status	Published - 2 Oct 2018

Keywords

Analysis of Variance
Animals
Appetite Depressants/metabolism
Appetite Regulation/drug effects
Arcuate Nucleus of Hypothalamus/cytology
Benzazepines/metabolism
Cell Line, Tumor
Eating/physiology
Feeding Behavior/physiology
Male
Mice
Mice, Knockout
Neurons/metabolism
Obesity/drug therapy
Receptor, Serotonin, 5-HT2C/metabolism
Serotonin 5-HT2 Receptor Agonists/metabolism
Solitary Nucleus/metabolism
Statistics, Nonparametric
Transfection

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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D'Agostino, G., Lyons, D., Cristiano, C., Lettieri, M., Olarte-Sanchez, C., Burke, L. K., Greenwald-Yarnell, M., Cansell, C., Doslikova, B., Georgescu, T., Martinez de Morentin, P. B., Myers, M. G., Rochford, J. J., & Heisler, L. K. (2018). Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake. Cell Metabolism, 28(4), 619-630.e5. https://doi.org/10.1016/j.cmet.2018.07.017, https://doi.org/10.1016/j.cmet.2018.07.017

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title = "Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake",

abstract = "To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.",

keywords = "Analysis of Variance, Animals, Appetite Depressants/metabolism, Appetite Regulation/drug effects, Arcuate Nucleus of Hypothalamus/cytology, Benzazepines/metabolism, Cell Line, Tumor, Eating/physiology, Feeding Behavior/physiology, Male, Mice, Mice, Knockout, Neurons/metabolism, Obesity/drug therapy, Receptor, Serotonin, 5-HT2C/metabolism, Serotonin 5-HT2 Receptor Agonists/metabolism, Solitary Nucleus/metabolism, Statistics, Nonparametric, Transfection",

author = "Giuseppe D'Agostino and David Lyons and Claudia Cristiano and Miriam Lettieri and Cristian Olarte-Sanchez and Burke, {Luke K} and Megan Greenwald-Yarnell and Celine Cansell and Barbora Doslikova and Teodora Georgescu and {Martinez de Morentin}, {Pablo Blanco} and Myers, {Martin G} and Rochford, {Justin J} and Heisler, {Lora K}",

note = "The authors wish to thank members of staff of the Medical Research Facility, University of Aberdeen, Ms. Raffaella Chianese and Dr. Susan Jalicy, for technical assistance. PX330 and PX552 plasmids were a gift from Prof. Feng Zhang (Massachusetts Institute of Technology, Massachusetts, USA). DREADD vectors were a gift from Prof. Bryan Roth (University of North Carolina at Chapel Hill, North Carolina, USA). PomcDsRED and PomcNEO mice were a gift from Prof. Malcolm Low (University of Michigan, Michigan, USA). Codes to analyze operant-responding for food were a gift from Dr. Vladimir Ordu{\~n}a Trujillo (National Autonomous University of Mexico, Mexico). This work was supported by the Wellcome Trust (L.K.H.; WT098012), Wellcome Trust and the University of Aberdeen (G.D.; 105625/Z/14/Z), Biotechnology and Biological Sciences Research Council (L.K.H., BB/K001418/1, BB/N017838/1; and J.J.R., BB/K017772/1), Medical Research Council (J.J.R., MR/L002620/1; G.D., MR/P009824/1; L.K.H., J.J.R., G.D., MC/PC/15077), British Society of Neuroendocrinology (G.D.), NIH and the Marilyn H. Vincent Foundation (M.G.M.; DK056731, DK034933).",

year = "2018",

month = oct,

day = "2",

doi = "10.1016/j.cmet.2018.07.017",

language = "English",

volume = "28",

pages = "619--630.e5",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "4",

}

D'Agostino, G, Lyons, D, Cristiano, C, Lettieri, M, Olarte-Sanchez, C, Burke, LK, Greenwald-Yarnell, M, Cansell, C, Doslikova, B, Georgescu, T, Martinez de Morentin, PB, Myers, MG, Rochford, JJ & Heisler, LK 2018, 'Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake', Cell Metabolism, vol. 28, no. 4, pp. 619-630.e5. https://doi.org/10.1016/j.cmet.2018.07.017, https://doi.org/10.1016/j.cmet.2018.07.017

TY - JOUR

T1 - Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

AU - D'Agostino, Giuseppe

AU - Lyons, David

AU - Cristiano, Claudia

AU - Lettieri, Miriam

AU - Olarte-Sanchez, Cristian

AU - Burke, Luke K

AU - Greenwald-Yarnell, Megan

AU - Cansell, Celine

AU - Doslikova, Barbora

AU - Georgescu, Teodora

AU - Martinez de Morentin, Pablo Blanco

AU - Myers, Martin G

AU - Rochford, Justin J

AU - Heisler, Lora K

N1 - The authors wish to thank members of staff of the Medical Research Facility, University of Aberdeen, Ms. Raffaella Chianese and Dr. Susan Jalicy, for technical assistance. PX330 and PX552 plasmids were a gift from Prof. Feng Zhang (Massachusetts Institute of Technology, Massachusetts, USA). DREADD vectors were a gift from Prof. Bryan Roth (University of North Carolina at Chapel Hill, North Carolina, USA). PomcDsRED and PomcNEO mice were a gift from Prof. Malcolm Low (University of Michigan, Michigan, USA). Codes to analyze operant-responding for food were a gift from Dr. Vladimir Orduña Trujillo (National Autonomous University of Mexico, Mexico). This work was supported by the Wellcome Trust (L.K.H.; WT098012), Wellcome Trust and the University of Aberdeen (G.D.; 105625/Z/14/Z), Biotechnology and Biological Sciences Research Council (L.K.H., BB/K001418/1, BB/N017838/1; and J.J.R., BB/K017772/1), Medical Research Council (J.J.R., MR/L002620/1; G.D., MR/P009824/1; L.K.H., J.J.R., G.D., MC/PC/15077), British Society of Neuroendocrinology (G.D.), NIH and the Marilyn H. Vincent Foundation (M.G.M.; DK056731, DK034933).

PY - 2018/10/2

Y1 - 2018/10/2

N2 - To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.

AB - To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT2CR) improve obesity. Here we probed the functional significance of 5-HT2CRs specifically within the brainstem nucleus of the solitary tract (5-HT2CRNTS) in feeding behavior. Selective activation of 5-HT2CRNTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT2CR agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMCARC), a subset of POMCNTS neurons co-expressed 5-HT2CRs and were activated by 5-HT2CR agonists. Knockdown of POMCNTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMCARC knockdown prevented the full anorectic effect. These data identify 5-HT2CRNTS as a sufficient subpopulation of 5-HT2CRs in reducing food intake when activated and reveal that 5-HT2CR agonist obesity medications require POMC within the NTS and ARC to reduce food intake.

KW - Analysis of Variance

KW - Animals

KW - Appetite Depressants/metabolism

KW - Appetite Regulation/drug effects

KW - Arcuate Nucleus of Hypothalamus/cytology

KW - Benzazepines/metabolism

KW - Cell Line, Tumor

KW - Eating/physiology

KW - Feeding Behavior/physiology

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Neurons/metabolism

KW - Obesity/drug therapy

KW - Receptor, Serotonin, 5-HT2C/metabolism

KW - Serotonin 5-HT2 Receptor Agonists/metabolism

KW - Solitary Nucleus/metabolism

KW - Statistics, Nonparametric

KW - Transfection

U2 - 10.1016/j.cmet.2018.07.017

DO - 10.1016/j.cmet.2018.07.017

M3 - Article

C2 - 30146485

SN - 1550-4131

VL - 28

SP - 619-630.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

Abstract

Keywords

UN SDGs

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