IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition |
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| Authors: | Eduardo R Ropelle Marcelo B Flores Dennys E Cintra Guilherme Z Rocha José R Pauli Joseane Morari Claudio T de Souza Juliana C Moraes Patrícia O Prada Dioze Guadagnini Rodrigo M Marin Alexandre G Oliveira Taize M Augusto Hernandes F Carvalho Lício A Velloso Mario J A Saad José B C Carvalheira |
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| Institution: | 1.Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil;2.Department of Anatomy, Cell Biology, Physiology and Biophysics, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil;University of Cambridge, United Kingdom |
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| Abstract: | Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKβ activation and endoplasmic reticulum (ER) stress in the hypothalamus. Here we show that physical exercise suppresses hyperphagia and associated hypothalamic IKKβ/NF-κB 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 IKKβ/NF-κB 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 IKKβ 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. |
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