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2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.
- Source :
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2010 Jun; Vol. 115 (2), pp. 482-91. Date of Electronic Publication: 2010 Feb 24. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Adipocytes metabolism
Animals
BALB 3T3 Cells
Cell Differentiation drug effects
Cell Survival drug effects
Down-Regulation drug effects
Fibroblasts drug effects
Fibroblasts metabolism
Gene Expression drug effects
Glucose metabolism
Humans
Insulin genetics
Insulin Resistance physiology
Mice
Receptors, Aryl Hydrocarbon metabolism
Signal Transduction drug effects
Adipocytes drug effects
Environmental Pollutants toxicity
Insulin metabolism
Polychlorinated Dibenzodioxins toxicity
Tumor Necrosis Factor-alpha biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0929
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Toxicological sciences : an official journal of the Society of Toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 20181658
- Full Text :
- https://doi.org/10.1093/toxsci/kfq052