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.
Highlights
Obesity and its associated metabolic abnormalities, including insulin resistance and cardiovascular disorders, have reached epidemic proportions
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 HFDIFNT mice than high-fat diet (HFD)-Control mice (Figure 3C).Taken together, our results suggest that interferon tau (IFNT) treatment effectively modulates obesity-associated insulin resistance at least by suppressing tissue inflammation
Interferon tau regulates macrophage activation in adipose tissues of HFD mice To further understand the impact of IFNT on adipose tissue immune cell populations that are major contributors to adipose tissue inflammatory status [4,5,6,13], we examined the relative proportions of T cells, B cells and macrophages in visceral stromal cells of visceral adipose tissues (VAT) from HFD-IFNT and HFD-Control mice
Summary
Obesity and its associated metabolic abnormalities, including insulin resistance and cardiovascular disorders, have reached epidemic proportions. Chronic low degree adipose tissue inflammation, accompanied by enhanced immune cell infiltration, is a hallmark of obesity and a crucial contributor to the pathogenesis of insulin resistance and metabolic diseases [1,2,3,4,5,6,7]. The infiltrated immune cells play critical roles in modulating obesity-associated adipose tissue inflammation. Adipose tissue macrophages (ATMs) undergo a phenotypic switch from anti-inflammatory status (M2) in the adipose tissues of lean individuals to a proinflammatory (M1) status in adipose tissues of obese subjects, which results in the development of tissue inflammation and systemic insulin resistance [12,13]. It has been demonstrated that activation of M2 macrophages can improve systemic insulin sensitivity and protect against development of cardiovascular diseases and type 2 diabetes [19,20]
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