title: IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.
abstract: Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKbeta/NF-kappaB activation by a mechanism dependent upon the pro-inflammatory cytokine interleukin (IL)-6. The disruption of hypothalamic-specific IL-6 action blocked the beneficial effects of exercise on the re-balance of food intake and insulin and leptin resistance. This molecular mechanism, mediated by physical activity, involves the anti-inflammatory protein IL-10, a core inhibitor of IKKbeta/NF-kappaB signaling and ER stress. We report that exercise and recombinant IL-6 requires IL-10 expression to suppress hyperphagia-related obesity. Moreover, in contrast to control mice, exercise failed to reverse the pharmacological activation of IKKbeta and ER stress in C3H/HeJ mice deficient in hypothalamic IL-6 and IL-10 signaling. Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.
authors.affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Flores
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.forename: Guilherme Z
authors.initials: GZ
authors.lastname: Rocha
authors.forename: José R
authors.initials: JR
authors.lastname: Pauli
authors.forename: Joseane
authors.initials: J
authors.lastname: Morari
authors.forename: Claudio T
authors.initials: CT
authors.lastname: de Souza
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Moraes
authors.forename: Patrícia O
authors.initials: PO
authors.lastname: Prada
authors.forename: Dioze
authors.initials: D
authors.lastname: Guadagnini
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Marin
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: Oliveira
authors.forename: Taize M
authors.initials: TM
authors.lastname: Augusto
authors.forename: Hernandes F
authors.initials: HF
authors.lastname: Carvalho
authors.forename: Lício A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004734:Energy Metabolism; D006963:Hyperphagia; D007031:Hypothalamus / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000378:metabolism*; D007328:Insulin / Q000502:physiology; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D020738:Leptin / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D020672:I-kappa B Proteins; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D016753:Interleukin-10
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