Hypothalamic IL6/ERK signaling controls lipid oxidation skeletal muscle

Orientador: Eduardo Rochete RopelleDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: O hipotálamo é uma estrutura do sistema nervoso central responsável por controlar diversas funções orgânicas. Recentes estudos apontam para uma intrigante relação entre o hipotálamo e o metabolismo do músculo esquelético. No presente estudo, demonstramos que a ação central da Interleucina 6 (IL6) é capaz de sensibilizar a musculatura esquelética aumentando oxidação de ácido graxo (OAG) em camundongos. Identificamos que essa ação ocorre através da ativação da via ERK 1/2 hipotalâmica, uma vez que a infusão intracerebroventricular (ICV) do inibidor farmacológico da ERK1/2, o PD98059, aboliu o efeito causado IL6 sobre OAG no músculo esquelético. Para avaliar a relevância fisiológica destes achados, observamos que o exercício físico foi capaz de estimular a via IL6/ERK1/2 no hipotálamo ventromedial (VMH) e ativar a OAG no músculo esquelético. Por outro lado, a inibição da ação central da IL6 através da injeção ICV do anticorpo anti-IL6 em camundongos, atenuou o efeito do exercício sobre a OAG no músculo. Adicionalmente, camundongos IL6 knockout (IL6KO), apresentaram deficiência na OAG no músculo quando submetidos ao exercício. Ao passo que a infusão exógena do recombinante da IL6 via ICV, restaurou o feito sobre ativação da OAG muscular nos animais IL6KO. Finalmente, identificamos que a comunicação entre o hipotálamo e o músculo esquelético ocorre através da via ?2AC adrenérgica, pois o uso do inibidor desta via, a Ioimbina, aboliu ativação da OAG promovido pela injeção ICV do recombinante de IL6, a mesma resposta observamos em camundongos duplo knockout para receptores adrenérgicos ?2AC. Coletivamente, estes resultados mostram que a via IL6/ERK1/2 hipotalâmica participa da OAG muscular em camundongosAbstract: The hypothalamus is a structure of the central nervous system responsible for controlling various organic functions. Recent studies point to an intriguing relationship between the hypothalamus and skeletal muscle metabolism. In this study, we demonstrated that the central action of interleukin 6 (IL6) is able to sensitize the increasing skeletal muscle fatty acid oxidation (FAO) in mice. We identified that this action occurs through the activation of the ERK 1/2 hypothalamic, since the infused intracerebroventricularly (ICV) of the pharmacological inhibitor of ERK1 / 2, PD98059, abolished the effect of IL6 central FAO in skeletal muscle. To evaluate the physiological relevance of these findings, we observed that exercise was able to stimulate via IL6 / ERK1 / 2 in the ventromedial hypothalamus (VMH) and activate the FAO in skeletal muscle. On the other hand central inhibition action of IL6 through ICV injection of anti-IL-6 antibody in mice attenuated the effect of exercise on muscle FAO. Additionally, IL6 knockout mice (IL6KO) showed deficiency in OAG in muscle when subjected to exercise. Whereas exogenous infusion of recombinant IL6 ICV restored the effect on activation of muscle FAO in IL6KO animals. Finally, we identified that the communication between the hypothalamus and skeletal muscle occurs through ?2AC adrenergic pathway, since the use of the inhibitor of this pathway, yohimbine, abolished FAO activation promoted by ICV injection of recombinant IL6, the same response observed in mice double knockout ?2AC adrenergic receptors. Collectively, these results show that the pathway IL6 / ERK1 / 2 hypothalamic participates in the FAO muscle in miceMestradoClinica MedicaMestra em Ciências2012/23006-1FAPES

High-fat diet during pregnancy and lactation impairs the cholinergic anti-inflammatory pathway in the liver and white adipose tissue of mouse offspring

14/18165-9; 13/10706-8476643/2012-0Cholinergic anti-inflammatory pathway (CAP) prevents inflammatory cytokines production. The main was to evaluate the effect of maternal obesity on cholinergic pathway in the offspring. Female mice were subjected to either standard chow (SC) or high-fat diet (HFD) during pregnancy and the lactation period. After weaning, only male offspring from HFD dams (HFD-O) and from SC dams (SC-O) were fed the SC diet. Key proteins of the CAP were downregulated and serum TNF-α was elevated in the HFD-O mice. STAT3 and NF-κB activation in HFD-O mice ICV injected with nicotine (agonist) were lower than SC-O mice. Basal cholinesterase activity was upregulated in HFD-O mice in both investigated tissues. Lipopolysaccharide increased TNF-α and IL-1β expression in the liver and WAT of SC-O mice, but this effect was greater in HFD-O mice. In conclusion these changes exacerbated cytokine production in response to LPS and contributed to the reduced sensitivity of the CAP.Cholinergic anti-inflammatory pathway (CAP) prevents inflammatory cytokines production. The main was to evaluate the effect of maternal obesity on cholinergic pathway in the offspring. Female mice were subjected to either standard chow (SC) or high-fat di422192202FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTIFICO E TECNOLOGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTIFICO E TECNOLOGICO14/18165-9; 13/10706-8476643/2012-014/18165-9; 13/10706-8476643/2012-0Les cages généralement utilisées en expérimentation animale peuvent empêcher les rats d'adopter la plupart des formes naturelles de comportement locomoteur. Ces animaux ont tendance a` adopter des habitudes sédentaires. Dans cette étude, nous démontrons