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 journalArticlepeer-review

2 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-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 languageEnglish
Pages (from-to)1319-1336
Number of pages18
JournalNature Metabolism
Volume5
Issue number8
DOIs
Publication statusPrint publication - Aug 2023
Externally publishedYes

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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