The serotonin transporter sustains human brown adipose tissue thermogenesis

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 ORCID: https://orcid.org/0000-0001-8218-8462, van Beek, EJR, Wakelin, SJ and Stimson, RH, 2023. The serotonin transporter sustains human brown adipose tissue thermogenesis. Nature Metabolism, 5 (8), pp. 1319-1336. ISSN 2522-5812

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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.

Item Type:	Journal article
Publication Title:	Nature Metabolism
Creators:	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. and Stimson, R.H.
Publisher:	Springer
Date:	August 2023
Volume:	5
Number:	8
ISSN:	2522-5812
Identifiers:	Number Type 10.1038/s42255-023-00839-2 DOI 1861744 Other
Rights:	© the author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	09 Jul 2025 13:21
Last Modified:	09 Jul 2025 13:21
URI:	https://irep.ntu.ac.uk/id/eprint/53923

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