期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 168, 期 2, 页码 435-444出版社
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2006.050699
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- NHLBI NIH HHS [1R01HL071146] Funding Source: Medline
Although tumor necrosis factor-alpha (TNF-alpha) is elevated in adipose tissue in obesity and may contribute to the cardiovascular and metabolic risks associated with this condition, the mechanisms leading to elevated TNF-alpha remain elusive. We hypothesized that autoamplification of TNF-alpha contributes to the maintenance of elevated TNF-alpha in obesity. Treatment of 3T3-L1 adipocytes with TNF-alpha, or injection of TNF-alpha into C57BL/6J mice, up-regulated TNF-alpha mRNA in adipocytes and in adipose tissues, respectively. Ob/ob male but not female mice lacking TNF-alpha receptors showed significantly lower levels of adipose TNF-alpha mRNA when compared with TNF-alpha receptor-expressing ob/ob mice. Thus, the lack of endogenous; TNF-alpha signaling reduced adipose TNF-alpha mRNA in ob/ob male mice. Additionally, hyperinsuhnemia potentiated this TNF-alpha-mediated autoamplification response in adipose tissues and in adipocytes in a synergistic and dose-dependent manner. Studies in which TNF-alpha was injected into lean mice lacking individual TNF-alpha receptors indicated that TNF-alpha autoamplification in adipose tissues was mediated primarily via the P55 TNF-alpha receptor whereas the p75 TNF-alpha receptor appeared to augment this response. Finally, TNF-alpha autoamplification in adipocytes occurred via the protein kinase C signaling pathway and the transcription factor nuclear factor-kappa B Thus, TNF-alpha can positively autoregulate its own biosynthesis in adipose tissue, contributing to the maintenance of elevated TNF-alpha in obesity.
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