Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis

Nat Med. 2015 Feb;21(2):166-72. doi: 10.1038/nm.3766. Epub 2014 Dec 8.


Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes 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, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Insulin Resistance / genetics*
  • Ion Channels / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism*
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity / genetics*
  • Obesity / metabolism
  • Serotonin / biosynthesis*
  • Thermogenesis / drug effects
  • Thermogenesis / genetics*
  • Tryptophan Hydroxylase / antagonists & inhibitors
  • Tryptophan Hydroxylase / genetics*
  • Uncoupling Protein 1


  • Ion Channels
  • Mitochondrial Proteins
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Serotonin
  • Tph1 protein, mouse
  • Tryptophan Hydroxylase