title: Hypothalamic S1P/S1PR1 axis controls energy homeostasis.
abstract: Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.
authors.affiliation: Laboratory of Molecular Biology of Exercise (LaBMEx). School of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccarias, 1300, CEP 13484-350 Limeira, São Paulo, Brazil.
authors.forename: Vagner R R
authors.initials: VR
authors.lastname: Silva
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Thayana O
authors.initials: TO
authors.lastname: Micheletti
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Pimentel
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Carlos K
authors.initials: CK
authors.lastname: Katashima
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Luciene
authors.initials: L
authors.lastname: Lenhare
authors.affiliation: Laboratory of Cell Signalling, Faculty of Medical Sciences, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Joseane
authors.initials: J
authors.lastname: Morari
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Maria Carolina S
authors.initials: MC
authors.lastname: Mendes
authors.affiliation: Laboratory of Cell Signalling, Faculty of Medical Sciences, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Guilherme Z
authors.initials: GZ
authors.lastname: Rocha
authors.affiliation: Laboratory of Exercise Biochemistry and Physiology, Health Sciences Unit, University of Southern Santa Catarina, CEP 88806-000 Criciúma, Santa Catarina, Brazil.
authors.forename: Claudio T
authors.initials: CT
authors.lastname: de Souza
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Patrícia O
authors.initials: PO
authors.lastname: Prada
authors.affiliation: Laboratory of Cell Signalling, Faculty of Medical Sciences, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.affiliation: Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
authors.affiliation: Laboratory of Molecular Biology of Exercise (LaBMEx). School of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccarias, 1300, CEP 13484-350 Limeira, São Paulo, Brazil.
authors.forename: José Rodrigo
authors.initials: JR
authors.lastname: Pauli
authors.affiliation: 1] Laboratory of Molecular Biology of Exercise (LaBMEx). School of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccarias, 1300, CEP 13484-350 Limeira, São Paulo, Brazil [2] Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil [3] Laboratory of Cell Signalling, Faculty of Medical Sciences, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.affiliation: 1] Laboratory of Molecular Biology of Exercise (LaBMEx). School of Applied Science, University of Campinas (UNICAMP), Rua Pedro Zaccarias, 1300, CEP 13484-350 Limeira, São Paulo, Brazil [2] Faculty of Medical Sciences, Department of Internal Medicine, University of Campinas (UNICAMP), CEP 13083-887 Campinas, São Paulo, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; C556330:S1pr1 protein, mouse; D050796:STAT3 Transcription Factor; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D011333:Pro-Opiomelanocortin; D013110:Sphingosine