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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 regulates macrophage activation in adipose tissues of mice fed a HFD.(A) Adipose tissue sections of HFD mice were stained with antibodies against F4/80, B220 and CD3 for macrophages, B cells and T cells, respectively. (B) Macrophage (M), B cell (B), CD4+ T cell (T4) and CD8+ T cell (T8) infiltration in VAT of HFD-fed mice was analyzed by flow cytometry with antibodies against F4/80, CD11b, B220, CD4 and CD8. (C) Macrophage subtypes in visceral fat stromal cells (VSC) of VAT were analyzed by flow cytometry using antibodies against F4/80, CD11b, CD11c and CD206. Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001.
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pone-0098835-g004: IFNT regulates macrophage activation in adipose tissues of mice fed a HFD.(A) Adipose tissue sections of HFD mice were stained with antibodies against F4/80, B220 and CD3 for macrophages, B cells and T cells, respectively. (B) Macrophage (M), B cell (B), CD4+ T cell (T4) and CD8+ T cell (T8) infiltration in VAT of HFD-fed mice was analyzed by flow cytometry with antibodies against F4/80, CD11b, B220, CD4 and CD8. (C) Macrophage subtypes in visceral fat stromal cells (VSC) of VAT were analyzed by flow cytometry using antibodies against F4/80, CD11b, CD11c and CD206. Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001.

Mentions: To further understand the impact of IFNT on adipose tissue immune cell populations that are major contributors to adipose tissue inflammatory status [4]-[6], [13], we examined the relative proportions of T cells, B cells and macrophages in visceral stromal cells of VAT from HFD-IFNT and HFD-Control mice. We first performed immunohistochemical staining on visceral adipose tissues isolated from both HFD-IFNT and HFD-Control groups with antibodies against F4/80 (macrophages), B220 (B cells) and CD3 (T cells). The results indicated that total numbers of macrophages, B cells and T cells infiltrated into VAT are comparable in HFD-IFNT mice and HFD-Control mice (Figure 4A). This was confirmed by further analysis using flow cytometry assays with the same set of antibodies. Consistent with results of immunohistochemical staining, the proportions of total macrophages (F4/80+CD11b+), B cells (B220+) and T cells (CD4+ or CD8+) were not significantly different between IFNT treated and control mice on either HFD (Figure4B) and LFD (FigureS3). Surprisingly, the distribution of macrophage subpopulations, i.e. M1 and M2 macrophages, was significantly altered by IFNT treatment. Compared to the HFD-Control mice, HFD-IFNT mice displayed dramatically decreasedproinflammatory M1 macrophages (F4/80+CD11b+CD206-CD11c+; Figure 4C)and a significant increase in anti-inflammatory M2 macrophages (F4/80+CD11b+CD206+CD11c-; Figure4C) which suggests a regulatory role for IFNT in macrophage polarization.


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 regulates macrophage activation in adipose tissues of mice fed a HFD.(A) Adipose tissue sections of HFD mice were stained with antibodies against F4/80, B220 and CD3 for macrophages, B cells and T cells, respectively. (B) Macrophage (M), B cell (B), CD4+ T cell (T4) and CD8+ T cell (T8) infiltration in VAT of HFD-fed mice was analyzed by flow cytometry with antibodies against F4/80, CD11b, B220, CD4 and CD8. (C) Macrophage subtypes in visceral fat stromal cells (VSC) of VAT were analyzed by flow cytometry using antibodies against F4/80, CD11b, CD11c and CD206. Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0098835-g004: IFNT regulates macrophage activation in adipose tissues of mice fed a HFD.(A) Adipose tissue sections of HFD mice were stained with antibodies against F4/80, B220 and CD3 for macrophages, B cells and T cells, respectively. (B) Macrophage (M), B cell (B), CD4+ T cell (T4) and CD8+ T cell (T8) infiltration in VAT of HFD-fed mice was analyzed by flow cytometry with antibodies against F4/80, CD11b, B220, CD4 and CD8. (C) Macrophage subtypes in visceral fat stromal cells (VSC) of VAT were analyzed by flow cytometry using antibodies against F4/80, CD11b, CD11c and CD206. Data are presented as mean ± SEM. *P<0.05, **P<0.001, ***P<0.0001.
Mentions: To further understand the impact of IFNT on adipose tissue immune cell populations that are major contributors to adipose tissue inflammatory status [4]-[6], [13], we examined the relative proportions of T cells, B cells and macrophages in visceral stromal cells of VAT from HFD-IFNT and HFD-Control mice. We first performed immunohistochemical staining on visceral adipose tissues isolated from both HFD-IFNT and HFD-Control groups with antibodies against F4/80 (macrophages), B220 (B cells) and CD3 (T cells). The results indicated that total numbers of macrophages, B cells and T cells infiltrated into VAT are comparable in HFD-IFNT mice and HFD-Control mice (Figure 4A). This was confirmed by further analysis using flow cytometry assays with the same set of antibodies. Consistent with results of immunohistochemical staining, the proportions of total macrophages (F4/80+CD11b+), B cells (B220+) and T cells (CD4+ or CD8+) were not significantly different between IFNT treated and control mice on either HFD (Figure4B) and LFD (FigureS3). Surprisingly, the distribution of macrophage subpopulations, i.e. M1 and M2 macrophages, was significantly altered by IFNT treatment. Compared to the HFD-Control mice, HFD-IFNT mice displayed dramatically decreasedproinflammatory M1 macrophages (F4/80+CD11b+CD206-CD11c+; Figure 4C)and a significant increase in anti-inflammatory M2 macrophages (F4/80+CD11b+CD206+CD11c-; Figure4C) which suggests a regulatory role for IFNT in macrophage polarization.

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