Format

Send to

Choose Destination
Toxicol Sci. 2010 Jun;115(2):482-91. doi: 10.1093/toxsci/kfq052. Epub 2010 Feb 24.

2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes.

Author information

1
Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Hyogo 650-0017, Japan. nishiums@med.kobe-u.ac.jp

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.

PMID:
20181658
DOI:
10.1093/toxsci/kfq052
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center