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^*

^*Corresponding author for this work

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

5 Citations (Scopus)

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-HT_2B 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
Number of pages	18
Journal	Nature Metabolism
Volume	5
Issue number	8
DOIs	https://doi.org/10.1038/s42255-023-00839-2
Publication status	Print publication - Aug 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Keywords

Sertraline/metabolism
Serotonin Plasma Membrane Transport Proteins/genetics
Thermogenesis/physiology
Animals
Serotonin/metabolism
Humans
Adipose Tissue, Brown/metabolism
Metabolic Diseases/metabolism
Mice
Obesity/metabolism

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Suchacki, K. J., Ramage, L. E., Kwok, T. C., Kelman, A., McNeill, B. T., Rodney, S., Keegan, M., Gray, C., MacNaught, G., Patel, D., Fletcher, A. M., Simpson, J. P., Carter, R. N., 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(8), 1319-1336. https://doi.org/10.1038/s42255-023-00839-2

@article{cd3d39284dfb432680e3cc0ab8567e06,

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.",

keywords = "Sertraline/metabolism, Serotonin Plasma Membrane Transport Proteins/genetics, Thermogenesis/physiology, Animals, Serotonin/metabolism, Humans, Adipose Tissue, Brown/metabolism, Metabolic Diseases/metabolism, Mice, Obesity/metabolism",

author = "Suchacki, {Karla J.} and Ramage, {Lynne E.} and Kwok, {T{\textquoteright}ng Choong} 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 Carter, {Roderick N.} 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 = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

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

language = "English",

volume = "5",

pages = "1319--1336",

journal = "Nature Metabolism",

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Suchacki, KJ, Ramage, LE, Kwok, TC, Kelman, A, McNeill, BT, Rodney, S, Keegan, M, Gray, C, MacNaught, G, Patel, D, Fletcher, AM, Simpson, JP, Carter, RN, 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, no. 8, 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 - Kwok, T’ng Choong

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 - Carter, Roderick N.

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.

PY - 2023/8

Y1 - 2023/8

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.

KW - Sertraline/metabolism

KW - Serotonin Plasma Membrane Transport Proteins/genetics

KW - Thermogenesis/physiology

KW - Animals

KW - Serotonin/metabolism

KW - Humans

KW - Adipose Tissue, Brown/metabolism

KW - Metabolic Diseases/metabolism

KW - Mice

KW - Obesity/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85166581898&partnerID=8YFLogxK

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

IS - 8

ER -

The serotonin transporter sustains human brown adipose tissue thermogenesis

Abstract

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Keywords

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