Transmembrane tumor necrosis factor-alpha sensitizes adipocytes to insulin

• Published in: Molecular and cellular endocrinology Vol. 406; pp. 78 - 86
• Main Authors: Zhou, Wenjing, Yang, Peng, Liu, Li, Zheng, Shan, Zeng, Qingling, Liang, Huifang, Zhu, Yazhen, Zhang, Zunyue, Wang, Jing, Yin, Bingjiao, Gong, Feili, Wu, Yiping, Li, Zhuoya
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05.05.2015
• Subjects: 3T3-L1 Cells; Adipocyte; Adipocytes - drug effects; Adipocytes - metabolism; Adipokines - metabolism; Adiponectin; Adult; Animals; Cell Membrane - drug effects; Cell Membrane - metabolism; Chemokine CCL2 - metabolism; Down-Regulation - drug effects; Female; Glucose - pharmacology; Glucose Transporter Type 4 - metabolism; Humans; IL-6; Insulin - pharmacology; Insulin Resistance; Interleukin-6 - metabolism; Lipolysis - drug effects; Mice; NF-kappa B - metabolism; PPAR gamma - metabolism; Protein Transport - drug effects; Signal Transduction - drug effects; Transmembrane TNF-α; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation - drug effects; Adipocyte; Transmembrane TNF-α; Insulin resistance; IL-6; Adiponectin
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2015.02.023

•tmTNF-α sensitizes adipocytes to insulin via promoting insulin signaling.•tmTNF-α downregulates proinflammatory adipokine secretion via inactivation of NF-κB.•tmTNF-α increases adiponectin expression and insulin sensitivity via PPAR-γ pathway.•tmTNF-α sensitizes adipocytes to insulin via forward signaling. 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.