title: Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis.
abstract: Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1b(f/f)ePet1(Cre) mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes.
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Institute of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: McGlashon
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Institute of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Gorecki
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Kozlowski
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Caitlin K
authors.initials: CK
authors.lastname: Thirnbeck
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Markan
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Kirstie L
authors.initials: KL
authors.lastname: Leslie
authors.affiliation: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Maya E
authors.initials: ME
authors.lastname: Kotas
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Department of Molecular Physiology & Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: George B
authors.initials: GB
authors.lastname: Richerson
authors.affiliation: Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; Institute of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. Electronic address: gillum@sund.ku.dk.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Gillum
mesh_terms: D002001:Adipose Tissue, Brown / Q000166:cytology / Q000294:innervation* / Q000502:physiology*; D052436:Adipose Tissue, White / Q000166:cytology / Q000294:innervation / Q000502:physiology; D000818:Animals; D001833:Body Temperature Regulation; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007473:Ion Channels / Q000235:genetics; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D059326:Serotonergic Neurons / Q000502:physiology*; D022722:Thermogenesis; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005947:Glucose