Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue

Abstract

Obesity is associated with chronic low-level inflammation, especially in fat tissues, which contributes to insulin resistance and type 2 diabetes mellitus (T2DM). Protein inhibitor of activated STAT 1 (PIAS1) modulates a variety of cellular processes such as cell proliferation and DNA damage responses. Particularly, PIAS1 functions in the innate immune system and is a key regulator of the inflammation cascade. However, whether PIAS1 is involved in the regulation of insulin sensitivity remains unknown. Here, we demonstrated that PIAS1 expression in white adipose tissue (WAT) was downregulated by c-Jun N-terminal kinase in prediabetic mice models. Overexpression of PIAS1 in inguinal WAT of prediabetic mice significantly improved systemic insulin sensitivity, whereas knockdown of PIAS1 in wild-type mice led to insulin resistance. Mechanistically, PIAS1 inhibited the activation of stress-induced kinases and the expression of nuclear factor-κB target genes in adipocytes, mainly including proinflammatory and chemotactic factors. In doing so, PIAS1 inhibited macrophage infiltration in adipose tissue, thus suppressing amplification of the inflammation cascade, which in turn improved insulin sensitivity. These results were further verified in a fat transplantation model. Our findings shed light on the critical role of PIAS1 in controlling insulin sensitivity and suggest a therapeutic potential of PIAS1 in T2DM.

High expression of miR-483-5p aggravates sepsis-induced acute lung injury

“…In addition, PIAS1 can be involved in the differentiation of hematopoietic stem cells and T cells (Zhang et al, 2017). Moreover, PIAS1 is critical for inhibiting inflammation in the lung and adipose (Liu et al, 2016;Liu et al, 2015). Liu et al have indicated that PIAS1 could suppress the level of IL-4 and IL-1β in the NF-κB pathway to inhibit the inflammation in the lung (Liu et al, 2016).…”

Protein inhibitor of activated STAT 4 (PIAS4) regulates pro-inflammatory transcription in hepatocytes by repressing SIRT1

“…Of note, a recent report echoes our finding that PIAS proteins play important roles in regulating metabolic inflammation. Liu et al examined expression patterns of PIAS proteins in adipose tissues in diabetic mice [37]; while PIAS1 levels was down-regulated, PIAS4 expression was up-regulated in db / db mice compared to wild type littermates. In addition, adenovirus-mediated PIAS1 over-expression alleviated inflammation in adipocytes although it remained untested whether PIAS4 depletion would have a similar effect.…”

Maintenance of Subcutaneous Fat Homeostasis Improves Systemic Metabolic Dysfunction in Obesity

“…It has been reported that PIAS1 accumulates at sites of DNA double-strand breaks and promotes DNA repair in a human osteosarcoma cell line (U2OS) (15). Although DNA damage presumably accumulates when subcutaneous fat is subjected to metabolic stress, Liu et al (10) report that PIAS1 is significantly reduced in iWAT. This difference may be due to cell context-dependent responses, so further studies will be needed to define the contribution of DNA damage in subcutaneous fat to obesity.…”

“…1). Using fat transplantation models, Liu et al (10) elegantly show that overexpression of PIAS1 could improve WAT-induced systemic metabolic dysfunction in obese animals. Taken together, these results indicate that PIAS1 is critically involved in the maintenance of systemic homeostasis through the regulation of both insulin sensitivity and inflammation in subcutaneous fat.…”

“…In this issue of Diabetes, Liu et al (10) report that the protein inhibitor of activated STAT 1 (PIAS1, also known as E3 SUMO-protein ligase PIAS1) in subcutaneous fat plays a critical role in the maintenance of metabolic homeostasis in obesity. They found that PIAS1 is a key regulator in the suppression of inguinal fat inflammation and systemic metabolic dysfunction in murine models of obesity.…”