SFEBES2021 Oral Communications Metabolism, Obesity and Diabetes (6 abstracts)
The serotonin transporter SLC6A4 protects human brown adipose tissue from serotonin-mediated suppression of thermogenesis.
T’ng Choong Kwok 1 , Karla Suchacki 1 , Lynne Ramage 1 , Alexandra Kelman 1 , Ben McNeill 1 , Stewart Rodney 1 , Matthew Keegan 1 , Calum Gray 1 , Jonathan Manning 1 , Gillian MacNaught 1 , Alison Fletcher 1 , Joanna Simpson 1 , Roderick Carter 1 , Nicholas Morton 1 , Natalie Homer 1 , Edwin van Beek 1 , Sonia Wakelin 2 & Roland Stimson 1
1University of Edinburgh, Edinburgh, United Kingdom; 2Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
The recent discovery of brown adipose tissue (BAT) in adult humans, which generates heat to maintain body temperature in a cold environment, offers an exciting new strategy to treat obesity and metabolic disease, but our knowledge of human BAT activation is limited. To identify novel pathways regulating human BAT, we undertook RNA sequencing of human brown and white adipocytes. The gene SLC6A4 (encoding the serotonin transporter SERT) was one of the most highly differentially expressed genes in brown adipocytes (>15-fold). In vitro, there was substantial 3H-serotonin uptake by human brown but not white adipocytes, this was abolished by the selective serotonin reuptake inhibitor (SSRI) sertraline. Serotonin inhibited uncoupled respiration in human primary brown adipocytes and decreased mRNA levels of uncoupling protein 1, this effect was mediated through the 5HT2B receptor. In vivo, SERT mRNA and protein levels were increased in human BAT versus white adipose tissue. Cold exposure acutely decreased circulating serotonin concentrations by ~40% in lean healthy subjects. A retrospective analysis of patients who had undergone PET/CT scanning at room temperature, revealed that no patients taking SSRIs had detectable 18F-fluorodeoxyglucose (18F-FDG) uptake by BAT compared with ~5% of matched controls, suggesting that SERT inhibition suppresses human BAT activation. Finally, we recruited 15 normal weight healthy subjects (age 24.7+/-1.0y, BMI 22.0+/-0.4kg/m2) to a double-blind randomised crossover study using the SSRI sertraline (50 mg daily for 7 days or placebo). BAT activity was quantified using 18F-FDG PET/MRI, thermal imaging and indirect calorimetry during cold exposure (17°C). Sertraline reduced 18F-FDG-uptake by BAT by ~40%, reduced supraclavicular skin temperature during cold and cold-induced thermogenesis compared with placebo, in keeping with decreased BAT activity. This research has identified a possible new mechanism of SSRI-driven weight gain and inhibition of peripheral serotonin synthesis may be a novel strategy to treat obesity-associated metabolic disease.
Volume 77
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Endocrine Abstracts
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