Transmembrane tumor necrosis factor-alpha sensitizes adipocytes to insulin.
Transmembrane TNF-α (tmTNF-α) acts both as a ligand, delivering 'forward signaling' via TNFR, and as a receptor, transducing 'reverse signaling'. The contradiction of available data regarding the effect of tmTNF-α on insulin resistance may be due to imbalance in both signals. Here, we demonstrated that high glucose-induced impairment of insulin-stimulated glucose uptake by 3T3-L1 adipocytes was concomitant with decreased tmTNF-α expression and increased soluble TNF-α (sTNF-α) secretion. However, when TACE was inhibited, preventing the conversion of tmTNF-α to sTNF-α, this insulin resistance was partially reversed, indicating a salutary role of tmTNF-α. Treatment of 3T3-L1 adipocytes with exogenous tmTNF-α promoted insulin-induced phosphorylation of IRS-1 and Akt, facilitated GLUT4 expression and membrane translocation, and increased glucose uptake while addition of sTNF-α resulted in the opposite effect. Furthermore, tmTNF-α downregulated the production of IL-6 and MCP-1 via NF-κB inactivation, as silencing of A20, an inhibitor for NF-κB, by siRNA, abolished this effect of tmTNF-α. However, tmTNF-α upregulated adiponectin expression through the PPAR-γ pathway, as inhibition of PPAR-γ by GW9662 abrogated both tmTNF-α-induced adiponectin transcription and glucose uptake. Our data suggest that tmTNF-α functions as an insulin sensitizer via forward signaling.
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Wenjing
W
Zhou
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Peng
P
Yang
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Li
L
Liu
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Shan
S
Zheng
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Hematology & Endocrinology, Fifth Hospital of Wuhan, Wuhan 430071, China.
Qingling
Q
Zeng
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Huifang
H
Liang
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Yazhen
Y
Zhu
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Zunyue
Z
Zhang
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Jing
J
Wang
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Bingjiao
B
Yin
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Feili
F
Gong
Department of Plastic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China.
Yiping
Y
Wu
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhuoyali@mails.tjmu.edu.cn.
Zhuoya
Z
Li
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D054392:Adipokines / Q000378:metabolism; D000328:Adult; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D054392:Adipokines; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051275:Glucose Transporter Type 4; D007328:Insulin; D015850:Interleukin-6; D016328:NF-kappa B; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose
Adipocyte; Adiponectin; IL-6; Insulin resistance; Transmembrane TNF-α