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Diabetes 51:3176-3188, 2002
© 2002 by the American Diabetes Association, Inc.
Profiling Gene Transcription In Vivo Reveals Adipose Tissue as an Immediate Target of Tumor Necrosis Factor-
Implications for Insulin Resistance
1 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
2 Department of Surgery, University of California, San Diego, California
3 Genome Center at the Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts
4 Department of Medicine, University of California, San Diego, California
5 San Diego VA Medical Center and the Whittier Institute for Diabetes, La Jolla, California
6 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
7 Dana-Farber Cancer Institute and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
Despite extensive studies implicating tumor necrosis factor (TNF)-
as a contributing cause of insulin resistance, the mechanism(s) by which TNF- alters energy metabolism in vivo and the tissue specificity of TNF- action are unclear. Here, we investigated the effects of TNF- infusion on gene expression and energy metabolism in adult rats. A 1-day TNF- treatment decreased overall insulin sensitivity and caused a 70% increase (P = 0.005) in plasma levels of free fatty acids (FFAs) and a 46% decrease (P = 0.01) in ACRP30. A 4-day TNF- infusion caused insulin resistance and significant elevation of plasma levels of FFAs and triglycerides and reduction of ACRP30. Plasma glucose concentration was not altered following TNF- infusion for up to 4 days. As revealed by oligonucleotide microarrays, TNF- evoked major and rapid changes in adipocyte gene expression, favoring FFA release and cytokine production, and fewer changes in liver gene expression, but favoring FFA and cholesterol synthesis and VLDL production. There was only a moderate repressive effect on skeletal muscle gene expression. We demonstrate that TNF- antagonizes the actions of insulin, at least in part, through regulation of adipocyte gene expression including reduction in ACRP30 mRNA and induction of lipolysis resulting in increased plasma FFAs. TNF- later alters systemic energy homeostasis that closely resembles the insulin resistance phenotype. Our data suggest that blockade of TNF- action in adipose tissue may prevent TNF--induced insulin resistance in vivo.
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