IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.
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.
Ropelle
Eduardo R
ER
Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Flores
Marcelo B
MB
Cintra
Dennys E
DE
Rocha
Guilherme Z
GZ
Pauli
José R
JR
Morari
Joseane
J
de Souza
Claudio T
CT
Moraes
Juliana C
JC
Prada
Patrícia O
PO
Guadagnini
Dioze
D
Marin
Rodrigo M
RM
Oliveira
Alexandre G
AG
Augusto
Taize M
TM
Carvalho
Hernandes F
HF
Velloso
Lício A
LA
Saad
Mario J A
MJ
Carvalheira
José B C
JB
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
D000893:Anti-Inflammatory Agents; D020672:I-kappa B Proteins; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D016753:Interleukin-10
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