Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China Institute of Stem Cell Research and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Diabetes. 2015 Dec;64(12):4061-74. doi: 10.2337/db15-0278. Epub 2015 Aug 31.
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.
肥胖与慢性低度炎症有关，尤其是在脂肪组织中，这会导致胰岛素抵抗和 2 型糖尿病（T2DM）。信号转导和转录激活因子 1（STAT1）的蛋白抑制剂（PIAS1）调节多种细胞过程，如细胞增殖和 DNA 损伤反应。特别是，PIAS1 在先天免疫系统中发挥作用，是炎症级联反应的关键调节因子。然而，PIAS1 是否参与胰岛素敏感性的调节尚不清楚。在这里，我们证明了在糖尿病前期小鼠模型中，c-Jun N 末端激酶下调了白色脂肪组织（WAT）中的 PIAS1 表达。过表达糖尿病前期小鼠腹股沟 WAT 中的 PIAS1 可显著改善全身胰岛素敏感性，而在野生型小鼠中敲低 PIAS1 则导致胰岛素抵抗。在机制上，PIAS1 抑制应激诱导激酶的激活和脂肪细胞中核因子-κB 靶基因的表达，主要包括促炎和趋化因子。这样，PIAS1 抑制了脂肪组织中巨噬细胞的浸润，从而抑制了炎症级联的放大，进而改善了胰岛素敏感性。这些结果在脂肪移植模型中得到了进一步验证。我们的研究结果揭示了 PIAS1 在控制胰岛素敏感性方面的关键作用，并表明 PIAS1 在 T2DM 中的治疗潜力。
