2,3,7,8-Tetrachlorodibenzo-p-Dioxin Impairs an Insulin Signaling Pathway through the Induction of Tumor Necrosis Factor-α in Adipocytes

• Published in: Toxicological sciences Vol. 115; no. 2; pp. 482 - 491
• Main Authors: Nishiumi, Shin, Yoshida, Masaru, Azuma, Takeshi, Yoshida, Ken-ichi, Ashida, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2010
• Subjects: adipocytes; Adipocytes - drug effects; Adipocytes - metabolism; AhR; Animals; BALB 3T3 Cells; Cell Differentiation - drug effects; Cell Survival - drug effects; Down-Regulation - drug effects; Environmental Pollutants - toxicity; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression - drug effects; Glucose - metabolism; Humans; Insulin - genetics; Insulin - metabolism; insulin resistance; Insulin Resistance - physiology; Mice; Polychlorinated Dibenzodioxins - toxicity; Receptors, Aryl Hydrocarbon - metabolism; Signal Transduction - drug effects; TCDD; TNF-α; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfq052

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes a wasting syndrome characterized by a loss of body weight accompanied by a decrease in adipose tissue weight, i.e., insulin resistance–like symptoms. Therefore, the effects of TCDD on an insulin signaling pathway in mature 3T3-L1 adipocytes were investigated to obtain insight into the underlying mechanisms. TCDD downregulated expression of insulin receptor β-subunit (IRβ), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (GLUT4) and decreased insulin-stimulated glucose uptake activity. TCDD also upregulated expression of TNF-α, one of insulin resistance–inducing factors. Anti-TNF-α neutralization antibody and silencing of TNF-α receptor 1 (TNFR1) diminished the TCDD-induced downregulation of IRβ, IRS1, and GLUT4. Moreover, the experiments using small interfering RNA for an aryl hydrocarbon receptor (AhR) revealed that the TCDD-evoked changes of IRβ, IRS1, GLUT4, and TNF-α were dependent on AhR. TCDD also stimulated the phosphorylation of extracellular signal–regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), and their inhibitors abrogated the TCDD-induced downregulation of IRβ, IRS1, and GLUT4; upregulation of TNF-α; and activation of NF-κB. Taken together, TCDD stimulates expression and secretion of TNF-α in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-α causes the downregulation of IRβ, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance.