Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue1,2, but its thermogenic potential is reduced with obesity and type 2 diabetes3,4,5 for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively6,7,8. Recent findings suggest that increased peripheral serotonin9 and polymorphisms in TPH1 are associated with obesity10; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.
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These studies were supported by grants from the Canadian Diabetes Association (CDA) (J.R.B.D., G.R.S.) the Canadian Institutes of Health Research (CIHR) (J.R.B.D., W.I.K., G.R.S.), Crohn's and Colitis Canada (W.I.K.), the Natural Sciences and Engineering Research Council of Canada (G.R.S.) and the Faculty of Health Sciences at McMaster University to the MAC-Obesity Research Program (G.R.S., K.M.M.). E.P.M. is a CDA Postdoctoral Fellow, M.D.F. is a CIHR Banting Postdoctoral Fellow, A.C. was a Canadian Liver Foundation Summer Student, S.M.H. is a Heart & Stroke Foundation of Canada and Alberta Innovates Health Solutions Postdoctoral Fellow, J.D.S. is a CDA Scholar and W.I.K. is a CIHR New Investigator. G.R.S. is a Canada Research Chair in Metabolism and Obesity and the J. Bruce Duncan Chair in Metabolic Diseases.
The authors declare no competing financial interests.
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Crane, J., Palanivel, R., Mottillo, E. et al. Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis. Nat Med 21, 166–172 (2015). https://doi.org/10.1038/nm.3766
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