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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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Related in: MedlinePlus

Hypothalamic insulin and leptin signaling after exercise.Western blots showing hypothalamic lysates from Wistar rats; (A) Hypothalamic IRβ, IRS-1, IRS-2, and Akt phosphorylation, (B) Hypothalamic Foxo1 phosphorylation. (C) 12-h food intake (kcal) after intrahypothalamic infusion of insulin in lean and diet-induced obesity (DIO) Wistar rats under resting conditions or after exercise (n = 6–8 animals per group). Western blots of five independent experiments showing hypothalamic lysates from Wistar rats; (D) Insulin-induced IRβ, IRS-1, IRS-2, Akt, and Foxo1 phosphorylation in the hypothalamus. (E) Subcellular fractionation was performed to evaluate the nuclear Foxo1 expression in the hypothalamus of lean and obese rats at 30 min after insulin infusion. (F) Hypothalamic Jak-2 and (G) STAT-3 tyrosine phosphorylation. (H) 12-h food intake (kcal) after intrahypothalamic infusion of leptin (n = 6–8 animals per group). Western blots showing hypothalamic lysates from Wistar rats; (I) Leptin-induced Jak2, IRS-1, IRS-2, and STAT3 tyrosine phosphorylation in the hypothalamus. (J) Subcellular fractionation was performed to evaluate the nuclear STAT3 expression in the hypothalamic cells of lean and obese rats 30 min after leptin infusion. Data are the means ± SEM. # p<0.05 versus respective lean group at rest; * p<0.05 versus obese group at rest. Lean animals (white bars) and obese animals (black bars).
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pbio-1000465-g002: Hypothalamic insulin and leptin signaling after exercise.Western blots showing hypothalamic lysates from Wistar rats; (A) Hypothalamic IRβ, IRS-1, IRS-2, and Akt phosphorylation, (B) Hypothalamic Foxo1 phosphorylation. (C) 12-h food intake (kcal) after intrahypothalamic infusion of insulin in lean and diet-induced obesity (DIO) Wistar rats under resting conditions or after exercise (n = 6–8 animals per group). Western blots of five independent experiments showing hypothalamic lysates from Wistar rats; (D) Insulin-induced IRβ, IRS-1, IRS-2, Akt, and Foxo1 phosphorylation in the hypothalamus. (E) Subcellular fractionation was performed to evaluate the nuclear Foxo1 expression in the hypothalamus of lean and obese rats at 30 min after insulin infusion. (F) Hypothalamic Jak-2 and (G) STAT-3 tyrosine phosphorylation. (H) 12-h food intake (kcal) after intrahypothalamic infusion of leptin (n = 6–8 animals per group). Western blots showing hypothalamic lysates from Wistar rats; (I) Leptin-induced Jak2, IRS-1, IRS-2, and STAT3 tyrosine phosphorylation in the hypothalamus. (J) Subcellular fractionation was performed to evaluate the nuclear STAT3 expression in the hypothalamic cells of lean and obese rats 30 min after leptin infusion. Data are the means ± SEM. # p<0.05 versus respective lean group at rest; * p<0.05 versus obese group at rest. Lean animals (white bars) and obese animals (black bars).

Mentions: Next, we evaluated whether exercise modulates insulin signaling in the hypothalamus. Western blot analysis revealed that IRβ, IRS-1, IRS-2, Akt, and FOXO1 phosphorylation were similar between the groups (Figure 2A and B). Although exercise did not change the basal levels of insulin signaling, we next performed intrahypothalamic insulin (200 mU) or its vehicle injection to evaluated food intake and insulin sensitivity after the SW Exe protocol. Overnutrition markedly reduced the ability of intrahypothalamic insulin infusion to reduce food intake, when compared to chow-fed animals; however, exercise restored the central effects of insulin on reduced food intake (Figure 2C). Using Western blotting analysis, we determined the effects of exercise on the insulin sensitivity in hypothalamic tissue. The high-fat diet impaired insulin-induced tyrosine phosphorylation of insulin receptor β (IRβ), insulin receptor substrate-1 (IRS-1), and IRS-2 in the hypothalamus (Figure 2D). Similar results were observed for the serine phosphorylation of Akt and FOXO1 (Figure 2D). Physical activity was able to restore insulin-induced hypothalamic IRβ, IRS-1, and IRS-2 tyrosine phosphorylation and insulin-induced hypothalamic Akt and FOXO1 serine phosphorylation in DIO rats (Figure 2D). Subcellular fraction of hypothalamic extract was then performed to evaluate the nuclear FOXO1 expression. Intrahypothalamic infusion of insulin reduced the nuclear FOXO1 expression in control rats, but insulin failed to reduce the nuclear FOXO1 expression in rats after overnutrition (Figure 2E). After exercise, insulin reduced the nuclear FOXO1 expression in neuronal cells of obese animals (52%), when compared to DIO at rest (Figure 2E).


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)

Hypothalamic insulin and leptin signaling after exercise.Western blots showing hypothalamic lysates from Wistar rats; (A) Hypothalamic IRβ, IRS-1, IRS-2, and Akt phosphorylation, (B) Hypothalamic Foxo1 phosphorylation. (C) 12-h food intake (kcal) after intrahypothalamic infusion of insulin in lean and diet-induced obesity (DIO) Wistar rats under resting conditions or after exercise (n = 6–8 animals per group). Western blots of five independent experiments showing hypothalamic lysates from Wistar rats; (D) Insulin-induced IRβ, IRS-1, IRS-2, Akt, and Foxo1 phosphorylation in the hypothalamus. (E) Subcellular fractionation was performed to evaluate the nuclear Foxo1 expression in the hypothalamus of lean and obese rats at 30 min after insulin infusion. (F) Hypothalamic Jak-2 and (G) STAT-3 tyrosine phosphorylation. (H) 12-h food intake (kcal) after intrahypothalamic infusion of leptin (n = 6–8 animals per group). Western blots showing hypothalamic lysates from Wistar rats; (I) Leptin-induced Jak2, IRS-1, IRS-2, and STAT3 tyrosine phosphorylation in the hypothalamus. (J) Subcellular fractionation was performed to evaluate the nuclear STAT3 expression in the hypothalamic cells of lean and obese rats 30 min after leptin infusion. Data are the means ± SEM. # p<0.05 versus respective lean group at rest; * p<0.05 versus obese group at rest. Lean animals (white bars) and obese animals (black bars).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2927536&req=5

pbio-1000465-g002: Hypothalamic insulin and leptin signaling after exercise.Western blots showing hypothalamic lysates from Wistar rats; (A) Hypothalamic IRβ, IRS-1, IRS-2, and Akt phosphorylation, (B) Hypothalamic Foxo1 phosphorylation. (C) 12-h food intake (kcal) after intrahypothalamic infusion of insulin in lean and diet-induced obesity (DIO) Wistar rats under resting conditions or after exercise (n = 6–8 animals per group). Western blots of five independent experiments showing hypothalamic lysates from Wistar rats; (D) Insulin-induced IRβ, IRS-1, IRS-2, Akt, and Foxo1 phosphorylation in the hypothalamus. (E) Subcellular fractionation was performed to evaluate the nuclear Foxo1 expression in the hypothalamus of lean and obese rats at 30 min after insulin infusion. (F) Hypothalamic Jak-2 and (G) STAT-3 tyrosine phosphorylation. (H) 12-h food intake (kcal) after intrahypothalamic infusion of leptin (n = 6–8 animals per group). Western blots showing hypothalamic lysates from Wistar rats; (I) Leptin-induced Jak2, IRS-1, IRS-2, and STAT3 tyrosine phosphorylation in the hypothalamus. (J) Subcellular fractionation was performed to evaluate the nuclear STAT3 expression in the hypothalamic cells of lean and obese rats 30 min after leptin infusion. Data are the means ± SEM. # p<0.05 versus respective lean group at rest; * p<0.05 versus obese group at rest. Lean animals (white bars) and obese animals (black bars).
Mentions: Next, we evaluated whether exercise modulates insulin signaling in the hypothalamus. Western blot analysis revealed that IRβ, IRS-1, IRS-2, Akt, and FOXO1 phosphorylation were similar between the groups (Figure 2A and B). Although exercise did not change the basal levels of insulin signaling, we next performed intrahypothalamic insulin (200 mU) or its vehicle injection to evaluated food intake and insulin sensitivity after the SW Exe protocol. Overnutrition markedly reduced the ability of intrahypothalamic insulin infusion to reduce food intake, when compared to chow-fed animals; however, exercise restored the central effects of insulin on reduced food intake (Figure 2C). Using Western blotting analysis, we determined the effects of exercise on the insulin sensitivity in hypothalamic tissue. The high-fat diet impaired insulin-induced tyrosine phosphorylation of insulin receptor β (IRβ), insulin receptor substrate-1 (IRS-1), and IRS-2 in the hypothalamus (Figure 2D). Similar results were observed for the serine phosphorylation of Akt and FOXO1 (Figure 2D). Physical activity was able to restore insulin-induced hypothalamic IRβ, IRS-1, and IRS-2 tyrosine phosphorylation and insulin-induced hypothalamic Akt and FOXO1 serine phosphorylation in DIO rats (Figure 2D). Subcellular fraction of hypothalamic extract was then performed to evaluate the nuclear FOXO1 expression. Intrahypothalamic infusion of insulin reduced the nuclear FOXO1 expression in control rats, but insulin failed to reduce the nuclear FOXO1 expression in rats after overnutrition (Figure 2E). After exercise, insulin reduced the nuclear FOXO1 expression in neuronal cells of obese animals (52%), when compared to DIO at rest (Figure 2E).

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