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IL-6 and IL-10 Anti-Inflammatory Activity Links Exercise to Hypothalamic Insulin and Leptin Sensitivity through IKKβ and ER Stress Inhibition

2010; Public Library of Science; Volume: 8; Issue: 8 Linguagem: Inglês

10.1371/journal.pbio.1000465

1545-7885

Eduardo R. Ropelle, Marcelo B.S. Flores, Dennys E. Cintra, Guilherme Z. Rocha, José Rodrigo Pauli, Joseane Morari, Cláudio Teodoro de Souza, Juliana C. Moraes, Patrícia O. Prada, Dioze Guadagnini, Rodrigo Marín-Navarrete, Alexandre G. Oliveira, Taize Machado Augusto, Hernandes F. Carvalho, Lı́cio A. Velloso, Mário J.A. Saad, José Barreto Campello Carvalheira,

Exercise and Physiological Responses

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.