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IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.

Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, de Souza CT, Moraes JC, Prada PO, Guadagnini D, Marin RM, Oliveira AG, Augusto TM, Carvalho HF, Velloso LA, Saad MJ, Carvalheira JB - PLoS Biol. (2010)

Bottom Line: Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus.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.Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

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.

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IL-6R localization in the hypothalamus of rats.(A) Immunohistochemistry was performed in the hypothalamic tissue of control rats, using IL-6 receptor (IL-6R)-specific antibody (green) and DAPI (blue), with 50× magnification. (B) Positive cells were quantified in different hypothalamic nuclei, § p<0.05 versus the other nuclei. (C) In situ hybridization showing the co-localization of IL-6R (red) with POMC, NPY, and AgRP (green) neuropeptides in the hypothalamus of control rats. Head arrows show neurons and arrows show endothelial cells using 20× and 63× magnification. (D) The dissection of hypothalamic arcuate nucleus of lean and obese rats was obtained as described in Experimental Procedures to evaluate the mRNA of POMC, NPY, and AgRP, using the real time PCR. Data are the means ± SEM. # p<0.05 versus respective control group at rest; * p<0.05 versus obese rats at rest. Lean animals (yellow bars) and obese (blue bars). (E) Confocal microscopy was performed to evaluate the co-localization of IL-6R (green) and IKKβ, PERK, and IRS-1 (red) in the arcuate nuclei of obese rats, with 200× magnification (scale bar, 20 µm).
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pbio-1000465-g004: IL-6R localization in the hypothalamus of rats.(A) Immunohistochemistry was performed in the hypothalamic tissue of control rats, using IL-6 receptor (IL-6R)-specific antibody (green) and DAPI (blue), with 50× magnification. (B) Positive cells were quantified in different hypothalamic nuclei, § p<0.05 versus the other nuclei. (C) In situ hybridization showing the co-localization of IL-6R (red) with POMC, NPY, and AgRP (green) neuropeptides in the hypothalamus of control rats. Head arrows show neurons and arrows show endothelial cells using 20× and 63× magnification. (D) The dissection of hypothalamic arcuate nucleus of lean and obese rats was obtained as described in Experimental Procedures to evaluate the mRNA of POMC, NPY, and AgRP, using the real time PCR. Data are the means ± SEM. # p<0.05 versus respective control group at rest; * p<0.05 versus obese rats at rest. Lean animals (yellow bars) and obese (blue bars). (E) Confocal microscopy was performed to evaluate the co-localization of IL-6R (green) and IKKβ, PERK, and IRS-1 (red) in the arcuate nuclei of obese rats, with 200× magnification (scale bar, 20 µm).

Mentions: Immunohistochemistry with an anti-IL-6 Receptor (IL-6R)-specific antibody showed that IL-6R is expressed in a majority of neurons in the arcuate nucleus (Figure 4A). These data were confirmed when we quantified the positive cells in arcuate (Arc), dorsomedial and ventromedial (DMH/VMH), paraventricular (PVN), and lateral (LH) nuclei of hypothalamus (Figure 4B). The in situ hybridization experiment revealed that IL-6R is expressed in both anorexigenic and orexigenic neurons of rats (Figure 4C).


IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKbeta and ER stress inhibition.

Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, de Souza CT, Moraes JC, Prada PO, Guadagnini D, Marin RM, Oliveira AG, Augusto TM, Carvalho HF, Velloso LA, Saad MJ, Carvalheira JB - PLoS Biol. (2010)

IL-6R localization in the hypothalamus of rats.(A) Immunohistochemistry was performed in the hypothalamic tissue of control rats, using IL-6 receptor (IL-6R)-specific antibody (green) and DAPI (blue), with 50× magnification. (B) Positive cells were quantified in different hypothalamic nuclei, § p<0.05 versus the other nuclei. (C) In situ hybridization showing the co-localization of IL-6R (red) with POMC, NPY, and AgRP (green) neuropeptides in the hypothalamus of control rats. Head arrows show neurons and arrows show endothelial cells using 20× and 63× magnification. (D) The dissection of hypothalamic arcuate nucleus of lean and obese rats was obtained as described in Experimental Procedures to evaluate the mRNA of POMC, NPY, and AgRP, using the real time PCR. Data are the means ± SEM. # p<0.05 versus respective control group at rest; * p<0.05 versus obese rats at rest. Lean animals (yellow bars) and obese (blue bars). (E) Confocal microscopy was performed to evaluate the co-localization of IL-6R (green) and IKKβ, PERK, and IRS-1 (red) in the arcuate nuclei of obese rats, with 200× magnification (scale bar, 20 µm).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2927536&req=5

pbio-1000465-g004: IL-6R localization in the hypothalamus of rats.(A) Immunohistochemistry was performed in the hypothalamic tissue of control rats, using IL-6 receptor (IL-6R)-specific antibody (green) and DAPI (blue), with 50× magnification. (B) Positive cells were quantified in different hypothalamic nuclei, § p<0.05 versus the other nuclei. (C) In situ hybridization showing the co-localization of IL-6R (red) with POMC, NPY, and AgRP (green) neuropeptides in the hypothalamus of control rats. Head arrows show neurons and arrows show endothelial cells using 20× and 63× magnification. (D) The dissection of hypothalamic arcuate nucleus of lean and obese rats was obtained as described in Experimental Procedures to evaluate the mRNA of POMC, NPY, and AgRP, using the real time PCR. Data are the means ± SEM. # p<0.05 versus respective control group at rest; * p<0.05 versus obese rats at rest. Lean animals (yellow bars) and obese (blue bars). (E) Confocal microscopy was performed to evaluate the co-localization of IL-6R (green) and IKKβ, PERK, and IRS-1 (red) in the arcuate nuclei of obese rats, with 200× magnification (scale bar, 20 µm).
Mentions: Immunohistochemistry with an anti-IL-6 Receptor (IL-6R)-specific antibody showed that IL-6R is expressed in a majority of neurons in the arcuate nucleus (Figure 4A). These data were confirmed when we quantified the positive cells in arcuate (Arc), dorsomedial and ventromedial (DMH/VMH), paraventricular (PVN), and lateral (LH) nuclei of hypothalamus (Figure 4B). The in situ hybridization experiment revealed that IL-6R is expressed in both anorexigenic and orexigenic neurons of rats (Figure 4C).

Bottom Line: Overnutrition caused by overeating is associated with insulin and leptin resistance through IKKbeta activation and endoplasmic reticulum (ER) stress in the hypothalamus.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.Hence, inflammatory signaling in the hypothalamus links beneficial physiological effects of exercise to the central action of insulin and leptin.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

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.

Show MeSH
Related in: MedlinePlus