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 Jr.; Justin J. Rochford; Lora K. Heisler

doi:10.1016/j.cmet.2018.07.017

Nucleus of the Solitary Tract Serotonin 5-HT_2C Receptors Modulate Food Intake

Giuseppe d'Agostino^* (Corresponding Author), 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 Jr., Justin J. Rochford, Lora K. Heisler^* (Corresponding Author)

^*Corresponding author for this work

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

90 Citations (Scopus)

17 Downloads (Pure)

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
Number of pages	18
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
Publication status	Published - 2 Oct 2018

Bibliographical 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 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).

Keywords

serotonin
5-HT2CR
lorcaserin
food intake
nucleus of the solitary tract
obesity

UN SDGs

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

Access to Document

10.1016/j.cmet.2018.07.017Licence: CC BY

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 4.53 MBLicence: CC BY

Cite this

d'Agostino, G., Lyons, D., Cristiano, C., Lettieri, M., Olarte-Sanchez, C., Burke, L. K., Greenwald-Yarnell, M., Cansell, C., Doslikova, B., Georgescu, T., Blanco Martinez de Morentin, P., Myers Jr., M. G., Rochford, J. J., & Heisler, L. K. (2018). Nucleus of the Solitary Tract Serotonin 5-HT_2C Receptors Modulate Food Intake. Cell Metabolism, 28(4), 619-630.e5. https://doi.org/10.1016/j.cmet.2018.07.017

d'Agostino, G, Lyons, D, Cristiano, C, Lettieri, M, Olarte-Sanchez, C, Burke, LK, Greenwald-Yarnell, M, Cansell, C, Doslikova, B, Georgescu, T, Blanco Martinez de Morentin, P, Myers Jr., MG, Rochford, JJ & Heisler, LK 2018, 'Nucleus of the Solitary Tract Serotonin 5-HT_2C Receptors Modulate Food Intake', Cell Metabolism, vol. 28, no. 4, pp. 619-630.e5. https://doi.org/10.1016/j.cmet.2018.07.017

@article{6aa7f382b25240e3a1e1194eb8b6a2ed,

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 = "serotonin, 5-HT2CR, lorcaserin, food intake, nucleus of the solitary tract, obesity",

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 {Blanco Martinez de Morentin}, Pablo and {Myers Jr.}, {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",

}

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 - Blanco Martinez de Morentin, Pablo

AU - Myers Jr., 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 - serotonin

KW - 5-HT2CR

KW - lorcaserin

KW - food intake

KW - nucleus of the solitary tract

KW - obesity

UR - https://www.cell.com/rights-sharing-embargoes

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 -