title: Key role of heat shock protein 90 in leptin-induced STAT3 activation and feeding regulation.
abstract: Leptin, an important regulator of the energy balance, acts on the brain to inhibit feeding. However, the mechanisms involved in leptin signalling have not yet been fully elucidated. Heat shock protein 90 (HSP90) is a molecular chaperone that is involved in regulating cellular homeostasis. In the present study, we investigated the possible involvement of HSP90 in leptin signal transduction.
  
  
  
  HEK293 and SH-SY5Y cell lines stably transfected with the Ob-Rb leptin receptor (HEK293 Ob-Rb, SH-SY5Y Ob-Rb) were used in the present study. Phosphorylation of JAK2 and STAT3 was analysed by western blotting. An HSP90 inhibitor was administered i.c.v. into rats and their food intake was analysed.
  
  
  
  The knock-down of HSP90 in the HEK293 Ob-Rb cell line attenuated leptin-induced JAK2 and STAT3 signalling. Moreover, leptin-induced JAK2/STAT3 phosphorylation was markedly attenuated by the HSP90 inhibitors geldanamycin, radicicol and novobiocin. However, these effects were not mediated through previously known factors, which are known to be involved in the development of leptin resistance, such as suppressor of cytokine signalling 3 or endoplasmic reticulum stress. The infusion of an HSP90 inhibitor into the CNS blunted the anorexigenic actions of leptin in rats (male Wister rat).
  
  
  
  HSP90 may be a novel factor involved in leptin-mediated signalling that is linked to anorexia.
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoi
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshiko
authors.initials: T
authors.lastname: Kohda
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Syu
authors.initials: S
authors.lastname: Matsuzaki
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Ishiguchi
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kuwamura
authors.affiliation: Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Akita
authors.affiliation: Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects*; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007276:Injections, Intraventricular; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D020738:Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C001277:geldanamycin