Protein Inhibitor of Activated STAT 1 (PIAS1) Protects Against Obesity-Induced Insulin Resistance by Inhibiting Inflammation Cascade in Adipose Tissue.
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.
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.
Yang
Y
Liu
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Xin
X
Ge
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Xin
X
Dou
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Liang
L
Guo
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.
Yuan
Y
Liu
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Shui-Rong
SR
Zhou
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Xiang-Bo
XB
Wei
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Shu-Wen
SW
Qian
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Hai-Yan
HY
Huang
Shanghai Key Laboratory of Female Reproductive Endocrine Related Disease, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Cong-Jian
CJ
Xu
Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
Wei-Ping
WP
Jia
Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education; Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China.
Yong-Jun
YJ
Dang
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.
Xi
X
Li
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 qqtang@shmu.edu.cn.
Qi-Qun
QQ
Tang
D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002633:Chemotaxis; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D011236:Prediabetic State / Q000209:etiology* / Q000517:prevention & control; D050828:Protein Inhibitors of Activated STAT / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; D011994:Recombinant Proteins; D048031:JNK Mitogen-Activated Protein Kinases