title: Hypothalamic S1P/S1PR1 axis controls energy homeostasis in Middle-Aged Rodents: the reversal effects of physical exercise.
abstract: Recently, we demonstrated that the hypothalamic S1PR1/STAT3 axis plays a critical role in the control of food consumption and energy expenditure in rodents. Here, we found that reduction of hypothalamic S1PR1 expression occurs in an age-dependent manner, and was associated with defective thermogenic signaling and weight gain. To address the physiological relevance of these findings, we investigated the effects of chronic and acute exercise on the hypothalamic S1PR1/STAT3 axis. Chronic exercise increased S1PR1 expression and STAT3 phosphorylation in the hypothalamus, restoring the anorexigenic and thermogenic signals in middle-aged mice. Acutely, exercise increased sphingosine-1-phosphate (S1P) levels in the cerebrospinal fluid (CSF) of young rats, whereas the administration of CSF from exercised young rats into the hypothalamus of middle-aged rats at rest was sufficient to reduce the food intake. Finally, the intracerebroventricular (ICV) administration of S1PR1 activators, including the bioactive lipid molecule S1P, and pharmacological S1PR1 activator, SEW2871, induced a potent STAT3 phosphorylation and anorexigenic response in middle-aged rats. Overall, these results suggest that hypothalamic S1PR1 is important for the maintenance of energy balance and provide new insights into the mechanism by which exercise controls the anorexigenic and thermogenic signals in the central nervous system during the aging process.
authors.affiliation: School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.|Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Vagner Ramon Rodrigues
authors.initials: VR
authors.lastname: Silva
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Carlos Kiyoshi
authors.initials: CK
authors.lastname: Katashima
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Carla G
authors.initials: CG
authors.lastname: Bueno Silva
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Luciene
authors.initials: L
authors.lastname: Lenhare
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Thayana Oliveira
authors.initials: TO
authors.lastname: Micheletti
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Rafael Ludemann
authors.initials: RL
authors.lastname: Camargo
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Ghezzi
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Juliana Alves
authors.initials: JA
authors.lastname: Camargo
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Alexandre Moura
authors.initials: AM
authors.lastname: Assis
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tobar
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Joseane
authors.initials: J
authors.lastname: Morari
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.affiliation: School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.
authors.forename: Leandro Pereira
authors.initials: LP
authors.lastname: Moura
authors.affiliation: School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.|Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.|CEPECE - Research Center of Sport Sciences, School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.
authors.forename: José Rodrigo
authors.initials: JR
authors.lastname: Pauli
authors.affiliation: School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.
authors.forename: Dennys Esper
authors.initials: DE
authors.lastname: Cintra
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.|Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 1308-970, Brazil.
authors.forename: Lício Augusto
authors.initials: LA
authors.lastname: Velloso
authors.affiliation: Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
authors.affiliation: School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.|Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil.|CEPECE - Research Center of Sport Sciences, School of Applied Sciences, University of Campinas, Limeira, SP, Brazil.|Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, 1308-970, Brazil.
authors.forename: Eduardo Rochete
authors.initials: ER
authors.lastname: Ropelle
mesh_terms: D015502:Absorptiometry, Photon; D002001:Adipose Tissue, Brown / Q000000981:diagnostic imaging; D000375:Aging / Q000502:physiology; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D007031:Hypothalamus / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D010101:Oxygen Consumption / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D000071256:Uncoupling Protein 1 / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C578616:S1PR1 protein, rat; D000081025:Sphingosine-1-Phosphate Receptors; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: S1PR1/STAT3; aging; exercise; hypothalamus