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© 2002 by the American Diabetes Association, Inc.
Tumor Necrosis Factor-
Suppresses Adipocyte-Specific Genes and Activates Expression of Preadipocyte Genes in 3T3-L1 Adipocytes
Nuclear Factor-
B Activation by TNF- Is Obligatory
1 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
2 Dana-Farber Cancer Institute and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
3 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
4 Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
Tumor necrosis factor-
(TNF-) is a contributing cause of the insulin resistance seen in obesity and obesity-linked type 2 diabetes, but the mechanism(s) by which TNF- induces insulin resistance is not understood. By using 3T3-L1 adipocytes and oligonucleotide microarrays, we identified 142 known genes reproducibly upregulated by at least threefold after 4 h and/or 24 h of TNF- treatment, and 78 known genes downregulated by at least twofold after 24 h of TNF- incubation. TNF--induced genes include transcription factors implicated in preadipocyte gene expression or NF-
B activation, cytokines and cytokine-induced proteins, growth factors, enzymes, and signaling molecules. Importantly, a number of adipocyte-abundant genes, including GLUT4, hormone sensitive lipase, long-chain fatty acyl-CoA synthase, adipocyte complement-related protein of 30 kDa, and transcription factors CCAAT/enhancer binding protein-, receptor retinoid X receptor-, and peroxisome profilerator-activated receptor 
were significantly downregulated by TNF- treatment. Correspondingly, 24-h exposure of 3T3-L1 adipocytes to TNF- resulted in reduced protein levels of GLUT4 and several insulin signaling proteins, including the insulin receptor, insulin receptor substrate 1 (IRS-1), and protein kinase B (AKT). Nuclear factor-B (NF-B) was activated within 15 min of TNF- addition. 3T3-L1 adipocytes expressing IB-DN, a nondegradable NF-B inhibitor, exhibited normal morphology, global gene expression, and insulin responses. However, absence of NF-B activation abolished suppression of >98% of the genes normally suppressed by TNF- and induction of 60–70% of the genes normally induced by TNF-. Moreover, extensive cell death occurred in IB-DN-expressing adipocytes after 2 h of TNF- treatment. Thus the changes in adipocyte gene expression induced by TNF- could lead to insulin resistance. Further, NF-B is an obligatory mediator of most of these TNF- responses.
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