The serotonin transporter sustains human brown adipose tissue thermogenesis

Karla J Suchacki; Lynne E Ramage; T'ng Choong Kwok; Alexandra Kelman; Ben T McNeill; Stewart Rodney; Matthew Keegan; Calum Gray; Gillian MacNaught; Dilip Patel; Alison M Fletcher; Joanna P Simpson; Roderick N Carter; Robert K Semple; Natalie Z M Homer; Nicholas M Morton; Edwin J R  van Beek; Sonia J Wakelin; Roland H Stimson

doi:10.1038/s42255-023-00839-2

The serotonin transporter sustains human brown adipose tissue thermogenesis

Karla J Suchacki, Lynne E Ramage, T'ng Choong Kwok, Alexandra Kelman, Ben T McNeill, Stewart Rodney, Matthew Keegan, Calum Gray, Gillian MacNaught, Dilip Patel, Alison M Fletcher, Joanna P Simpson, Roderick N Carter, Robert K Semple, Natalie Z M Homer, Nicholas M Morton, Edwin J R van Beek, Sonia J Wakelin, Roland H Stimson

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

Abstract

Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here, we show that the serotonin transporter SERT, encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin’s suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

Original language	English
Pages (from-to)	1319-1336
Journal	Nature Metabolism
Volume	5
DOIs	https://doi.org/10.1038/s42255-023-00839-2
Publication status	Published - 3 Aug 2023

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NM_SERT regulation of human BAT_060623_clean_versionAccepted author manuscript, 285 KBLicence: Creative Commons: Attribution (CC-BY)
The serotonin transporter sustains human brown adipose tissue thermogenesisFinal published version, 9.9 MBLicence: Creative Commons: Attribution (CC-BY)

Research Excellence Award Number 3
Baker, A. (Principal Investigator)
UK-based charities
1/04/19 → 31/03/24
Project: Research
Causes and Consequences of Pathological Adipose Remodelling
Semple, R. (Principal Investigator)
UK-based charities
1/06/18 → 31/05/23
Project: Research
Regulation of brown adipose tissue and cold induced thermogenesis in humans
Stimson, R. (Principal Investigator)
UK central government bodies/local authorities, health and hospital authorities
1/03/18 → 30/06/23
Project: Research

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI
Homer, N. (Manager), Denham, S. (Other) & Simpson, J. (Other)
School of Neurological and Cardiovascular Sciences
Facility/equipment: Facility
Edinburgh Imaging Facility
Grant, A. (Manager), van Beek, E. (Manager) & Semple, S. (Manager)
School of Neurological and Cardiovascular Sciences
Facility/equipment: Facility
Image Analysis Core
MacGillivray, T. (Manager) & Gray, C. (Other)
Work Enabled by Edinburgh Clinical Research Facility
Facility/equipment: Facility

Cite this

Suchacki, K. J., Ramage, L. E., Choong Kwok, T., Kelman, A., McNeill, B. T., Rodney, S., Keegan, M., Gray, C., MacNaught, G., Patel, D., Fletcher, A. M., Simpson, J. P., N Carter, R., Semple, R. K., Homer, N. Z. M., Morton, N. M., van Beek, E. J. R., Wakelin, S. J., & Stimson, R. H. (2023). The serotonin transporter sustains human brown adipose tissue thermogenesis. Nature Metabolism, 5, 1319-1336. https://doi.org/10.1038/s42255-023-00839-2

@article{aaac71a1a5444026ac7cd26a8688bd73,

title = "The serotonin transporter sustains human brown adipose tissue thermogenesis",

abstract = "Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here, we show that the serotonin transporter SERT, encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin{\textquoteright}s suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.",

author = "Suchacki, \{Karla J\} and Ramage, \{Lynne E\} and \{Choong Kwok\}, T'ng and Alexandra Kelman and McNeill, \{Ben T\} and Stewart Rodney and Matthew Keegan and Calum Gray and Gillian MacNaught and Dilip Patel and Fletcher, \{Alison M\} and Simpson, \{Joanna P\} and \{N Carter\}, Roderick and Semple, \{Robert K\} and Homer, \{Natalie Z M\} and Morton, \{Nicholas M\} and \{van Beek\}, \{Edwin J R\} and Wakelin, \{Sonia J\} and Stimson, \{Roland H\}",

note = "Funding Information: This work was supported by grants from the Medical Research Council (MR/K010271/1, MR/S035761/1), the Chief Scientist Office (SCAF/17/02) and the British Heart Foundation (RE/18/5/34216) to R.H.S. We acknowledge the financial support of NHS Research Scotland (NRS) for the Mass Spectrometry Core (RRID:SCR\_021833) through the Edinburgh Clinical Research Facility (ECRF) with data collected on the AB SCIEX QTRAP 6500+ instrument (RRID:SCR\_021831). R.K.S. is supported by the Wellcome Trust (grant 210752/Z/18/Z). We thank L. Grisales-Pastor and the other nurses at the Clinical Research Facility, and the radiographers and S. Semple at the Edinburgh Imaging Facility for their assistance. We thank J. Manning at the Centre for Regenerative Medicine at the University of Edinburgh for his assistance. We acknowledge the technical support of S. Denham and P. Lee at the Mass Spectrometry Core facility, L. Murphy, A. Fawkes, A. Coutts and R. Clark at the ECRF Genetics Core and M. Sinton at the University of Glasgow. We also acknowledge the assistance of C. Scheele at the University of Copenhagen and the NHS Scotland Pharmaceutical {\textquoteleft}Specials{\textquoteright} Service. Recruitment to one of the human studies was facilitated by SHARE, the Scottish Health Research Register. SHARE is supported by NRS and the Chief Scientist Office. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

day = "3",

doi = "10.1038/s42255-023-00839-2",

language = "English",

volume = "5",

pages = "1319--1336",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer",

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Suchacki, KJ, Ramage, LE, Choong Kwok, T, Kelman, A, McNeill, BT, Rodney, S, Keegan, M, Gray, C, MacNaught, G, Patel, D, Fletcher, AM, Simpson, JP , N Carter, R , Semple, RK , Homer, NZM, Morton, NM, van Beek, EJR, Wakelin, SJ & Stimson, RH 2023, 'The serotonin transporter sustains human brown adipose tissue thermogenesis', Nature Metabolism, vol. 5, pp. 1319-1336. https://doi.org/10.1038/s42255-023-00839-2

TY - JOUR

T1 - The serotonin transporter sustains human brown adipose tissue thermogenesis

AU - Suchacki, Karla J

AU - Ramage, Lynne E

AU - Choong Kwok, T'ng

AU - Kelman, Alexandra

AU - McNeill, Ben T

AU - Rodney, Stewart

AU - Keegan, Matthew

AU - Gray, Calum

AU - MacNaught, Gillian

AU - Patel, Dilip

AU - Fletcher, Alison M

AU - Simpson, Joanna P

AU - N Carter, Roderick

AU - Semple, Robert K

AU - Homer, Natalie Z M

AU - Morton, Nicholas M

AU - van Beek, Edwin J R

AU - Wakelin, Sonia J

AU - Stimson, Roland H

N1 - Funding Information: This work was supported by grants from the Medical Research Council (MR/K010271/1, MR/S035761/1), the Chief Scientist Office (SCAF/17/02) and the British Heart Foundation (RE/18/5/34216) to R.H.S. We acknowledge the financial support of NHS Research Scotland (NRS) for the Mass Spectrometry Core (RRID:SCR_021833) through the Edinburgh Clinical Research Facility (ECRF) with data collected on the AB SCIEX QTRAP 6500+ instrument (RRID:SCR_021831). R.K.S. is supported by the Wellcome Trust (grant 210752/Z/18/Z). We thank L. Grisales-Pastor and the other nurses at the Clinical Research Facility, and the radiographers and S. Semple at the Edinburgh Imaging Facility for their assistance. We thank J. Manning at the Centre for Regenerative Medicine at the University of Edinburgh for his assistance. We acknowledge the technical support of S. Denham and P. Lee at the Mass Spectrometry Core facility, L. Murphy, A. Fawkes, A. Coutts and R. Clark at the ECRF Genetics Core and M. Sinton at the University of Glasgow. We also acknowledge the assistance of C. Scheele at the University of Copenhagen and the NHS Scotland Pharmaceutical ‘Specials’ Service. Recruitment to one of the human studies was facilitated by SHARE, the Scottish Health Research Register. SHARE is supported by NRS and the Chief Scientist Office. Publisher Copyright: © 2023, The Author(s).

PY - 2023/8/3

Y1 - 2023/8/3

N2 - Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here, we show that the serotonin transporter SERT, encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin’s suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

AB - Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here, we show that the serotonin transporter SERT, encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin’s suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.

U2 - 10.1038/s42255-023-00839-2

DO - 10.1038/s42255-023-00839-2

M3 - Article

C2 - 37537371

SN - 2522-5812

VL - 5

SP - 1319

EP - 1336

JO - Nature Metabolism

JF - Nature Metabolism

ER -

The serotonin transporter sustains human brown adipose tissue thermogenesis

Abstract

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Projects

Research Excellence Award Number 3

Causes and Consequences of Pathological Adipose Remodelling

Regulation of brown adipose tissue and cold induced thermogenesis in humans

Equipment

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI

Edinburgh Imaging Facility

Image Analysis Core

Cite this