2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.
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 beta-subunit (IRbeta), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (GLUT4) and decreased insulin-stimulated glucose uptake activity. TCDD also upregulated expression of TNF-alpha, one of insulin resistance-inducing factors. Anti-TNF-alpha neutralization antibody and silencing of TNF-alpha receptor 1 (TNFR1) diminished the TCDD-induced downregulation of IRbeta, IRS1, and GLUT4. Moreover, the experiments using small interfering RNA for an aryl hydrocarbon receptor (AhR) revealed that the TCDD-evoked changes of IRbeta, IRS1, GLUT4, and TNF-alpha 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 IRbeta, IRS1, and GLUT4; upregulation of TNF-alpha; and activation of NF-kappaB. Taken together, TCDD stimulates expression and secretion of TNF-alpha in adipocytes through activation of AhR, ERK1/2, and JNK, and the secreted TNF-alpha causes the downregulation of IRbeta, IRS1, and GLUT4 through TNFR1, resulting in insulin resistance.
Nishiumi
Shin
S
Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan. nishiums@med.kobe-u.ac.jp
Yoshida
Masaru
M
Azuma
Takeshi
T
Yoshida
Ken-Ichi
K
Ashida
Hitoshi
H
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D041702:BALB 3T3 Cells; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D004785:Environmental Pollutants; D007328:Insulin; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose