title: Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.
abstract: 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.
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. [2] Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Crane
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. [2] Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. [3] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rengasamy
authors.initials: R
authors.lastname: Palanivel
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bujak
authors.affiliation: 1] Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. [2] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Regje M
authors.initials: RM
authors.lastname: Blümer
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Julian M
authors.initials: JM
authors.lastname: Yabut
authors.affiliation: 1] Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. [2] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jean-Eric
authors.identifier: 0000000230189719
authors.initials: JE
authors.lastname: Ghia
authors.affiliation: Cardiovascular Research Centre, Alberta Diabetes Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Shereen M
authors.initials: SM
authors.lastname: Hamza
authors.affiliation: Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Morrison
authors.affiliation: 1] Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. [2] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.affiliation: Cardiovascular Research Centre, Alberta Diabetes Institute, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: 1] Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada. [2] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Waliul I
authors.initials: WI
authors.lastname: Khan
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada. [2] Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis*; D022722:Thermogenesis / Q000187:drug effects / Q000235:genetics*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics*; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase