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Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization.

Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B - PLoS ONE (2014)

Bottom Line: Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes.Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways.Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes. Currently available type I interferons for therapeutic immunomodulation are accompanied by high cytotoxicity and therefore in this study we have examined anti-inflammatory effects of interferon tau (IFNT), a member of the type I interferon family with low cellular toxicity even at high doses. Using a diet-induced obesity mouse model, we observed enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, which was accompanied by a significant decrease in secretion of proinflammatory cytokines and elevated anti-inflammatory macrophages (M2) in adipose tissue. Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways. Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

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IFNT reduces obesity-associated adipose tissue inflammation.(A) Visceral adipose tissues (VAT) weight and adiposity of mice after 12-week HFD feeding. (B) Nuclear factor-κB (NFκB) activation in VAT of HFD mice. Western blotting was performed with antibodies against p65 and phosphorylated p65 (Pp65; n = 3). C, control; T, IFNT. (C) Activation of c-Jun N-terminal kinase (JNK) signaling pathway in VAT of HFD mice. Fluorescent-labeled beads conjugated with antibodies against total JNK (tJNK) and phosphorylated JNK (phospho JNK) in VAT were measured using the Bio-Plex® MAGPIX™ multiplex reader. MFI, medium fluorescence intensity. Data are presented as mean ± SEM. *P<0.05.
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pone-0098835-g002: IFNT reduces obesity-associated adipose tissue inflammation.(A) Visceral adipose tissues (VAT) weight and adiposity of mice after 12-week HFD feeding. (B) Nuclear factor-κB (NFκB) activation in VAT of HFD mice. Western blotting was performed with antibodies against p65 and phosphorylated p65 (Pp65; n = 3). C, control; T, IFNT. (C) Activation of c-Jun N-terminal kinase (JNK) signaling pathway in VAT of HFD mice. Fluorescent-labeled beads conjugated with antibodies against total JNK (tJNK) and phosphorylated JNK (phospho JNK) in VAT were measured using the Bio-Plex® MAGPIX™ multiplex reader. MFI, medium fluorescence intensity. Data are presented as mean ± SEM. *P<0.05.

Mentions: There is compelling evidencefor causal effects of obesity-associated chronic inflammation, especially in adipose tissues of obese individuals, and the pathogenesis of systemic insulin resistance [1]. Although HFD-IFNT and HFD-Control mice had similar degrees of adiposity (Figure 2A), IFNT treatment suppressed activation of NFκBactivation as evidenced by lower p65 phosphorylation and JNK pathway activity as evidenced by decreased phosphorylated-JNK in VAT of HFD mice (Figure 2B, C). In addition, HFD-IFNT mice displayed lower levels of proinflammatory cytokines, namely IL-1β, IL-6 and TNF-α, and increased expression of the anti-inflammatory cytokine IL-10 in adipose tissuecompared to HFD-Control mice (Figure 3A). However, the expressionof CCL-2 in adipose tissues isolated from HFD mice was not affected by IFNT treatment (Figure 3A). Expression of adiponectin, an adipokine negatively associated with obesity, was induced by IFNT treatment in HFD mice compared to the control group (Figure3A). We also detected decreasedconcentrations ofCCL2 and TNF-α and elevated concentration of IL-10 in plasma of HFD-IFNT mice compared to HFD-Control mice (Figure 3B). We further determined the impact of IFNT treatment on the insulin signaling pathway in adipose tissues of HFD mice. In the ex vivoanalysis of insulin signaling, we detected an increase in the abundance of phosphorylated Akt protein in isolated mature adipocytes treated with insulin compared to that in mature adipocytes from mice that were not treated with insulin. This result indicates that insulin successfully activated the intracellular insulin signaling pathway in the isolated mature adipocytes.Interestingly, total Akt protein and its insulin-responsive phosphorylation were both greater in mature adipocytes isolated from HFD-IFNT mice than HFD-Control mice (Figure 3C).Taken together, our results suggest that IFNT treatment effectively modulates obesity-associated insulin resistance at least by suppressing tissue inflammation.


Interferon tau alleviates obesity-induced adipose tissue inflammation and insulin resistance by regulating macrophage polarization.

Ying W, Kanameni S, Chang CA, Nair V, Safe S, Bazer FW, Zhou B - PLoS ONE (2014)

IFNT reduces obesity-associated adipose tissue inflammation.(A) Visceral adipose tissues (VAT) weight and adiposity of mice after 12-week HFD feeding. (B) Nuclear factor-κB (NFκB) activation in VAT of HFD mice. Western blotting was performed with antibodies against p65 and phosphorylated p65 (Pp65; n = 3). C, control; T, IFNT. (C) Activation of c-Jun N-terminal kinase (JNK) signaling pathway in VAT of HFD mice. Fluorescent-labeled beads conjugated with antibodies against total JNK (tJNK) and phosphorylated JNK (phospho JNK) in VAT were measured using the Bio-Plex® MAGPIX™ multiplex reader. MFI, medium fluorescence intensity. Data are presented as mean ± SEM. *P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4048269&req=5

pone-0098835-g002: IFNT reduces obesity-associated adipose tissue inflammation.(A) Visceral adipose tissues (VAT) weight and adiposity of mice after 12-week HFD feeding. (B) Nuclear factor-κB (NFκB) activation in VAT of HFD mice. Western blotting was performed with antibodies against p65 and phosphorylated p65 (Pp65; n = 3). C, control; T, IFNT. (C) Activation of c-Jun N-terminal kinase (JNK) signaling pathway in VAT of HFD mice. Fluorescent-labeled beads conjugated with antibodies against total JNK (tJNK) and phosphorylated JNK (phospho JNK) in VAT were measured using the Bio-Plex® MAGPIX™ multiplex reader. MFI, medium fluorescence intensity. Data are presented as mean ± SEM. *P<0.05.
Mentions: There is compelling evidencefor causal effects of obesity-associated chronic inflammation, especially in adipose tissues of obese individuals, and the pathogenesis of systemic insulin resistance [1]. Although HFD-IFNT and HFD-Control mice had similar degrees of adiposity (Figure 2A), IFNT treatment suppressed activation of NFκBactivation as evidenced by lower p65 phosphorylation and JNK pathway activity as evidenced by decreased phosphorylated-JNK in VAT of HFD mice (Figure 2B, C). In addition, HFD-IFNT mice displayed lower levels of proinflammatory cytokines, namely IL-1β, IL-6 and TNF-α, and increased expression of the anti-inflammatory cytokine IL-10 in adipose tissuecompared to HFD-Control mice (Figure 3A). However, the expressionof CCL-2 in adipose tissues isolated from HFD mice was not affected by IFNT treatment (Figure 3A). Expression of adiponectin, an adipokine negatively associated with obesity, was induced by IFNT treatment in HFD mice compared to the control group (Figure3A). We also detected decreasedconcentrations ofCCL2 and TNF-α and elevated concentration of IL-10 in plasma of HFD-IFNT mice compared to HFD-Control mice (Figure 3B). We further determined the impact of IFNT treatment on the insulin signaling pathway in adipose tissues of HFD mice. In the ex vivoanalysis of insulin signaling, we detected an increase in the abundance of phosphorylated Akt protein in isolated mature adipocytes treated with insulin compared to that in mature adipocytes from mice that were not treated with insulin. This result indicates that insulin successfully activated the intracellular insulin signaling pathway in the isolated mature adipocytes.Interestingly, total Akt protein and its insulin-responsive phosphorylation were both greater in mature adipocytes isolated from HFD-IFNT mice than HFD-Control mice (Figure 3C).Taken together, our results suggest that IFNT treatment effectively modulates obesity-associated insulin resistance at least by suppressing tissue inflammation.

Bottom Line: Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes.Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways.Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Chronic adipose tissue inflammation is a hallmark of obesity-induced insulin resistance and anti-inflammatory agents can benefit patients with obesity-associated syndromes. Currently available type I interferons for therapeutic immunomodulation are accompanied by high cytotoxicity and therefore in this study we have examined anti-inflammatory effects of interferon tau (IFNT), a member of the type I interferon family with low cellular toxicity even at high doses. Using a diet-induced obesity mouse model, we observed enhanced insulin sensitivity in obese mice administered IFNT compared to control mice, which was accompanied by a significant decrease in secretion of proinflammatory cytokines and elevated anti-inflammatory macrophages (M2) in adipose tissue. Further investigations revealed that IFNT is a potent regulator of macrophage activation that favors anti-inflammatory responses as evidenced by activation of associated surface antigens, production of anti-inflammatory cytokines, and activation of selective cell signaling pathways. Thus, our study demonstrates, for the first time, that IFNT can significantly mitigate obesity-associated systemic insulin resistance and tissue inflammation by controlling macrophage polarization, and thus IFNT can be a novel bio-therapeutic agent for treating obesity-associated syndromes and type 2 diabetes.

Show MeSH
Related in: MedlinePlus