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(American Journal of Pathology. 2006;168:435-444.)
© 2006 American Society for Investigative Pathology

Autoamplification of Tumor Necrosis Factor-{alpha}

A Potential Mechanism for the Maintenance of Elevated Tumor Necrosis Factor-{alpha} in Male but Not Female Obese Mice

Jaap G. Neels*, Manjula Pandey*, Gökhan S. Hotamisligil{dagger} and Fahumiya Samad{ddagger}

From the Division of Vascular Biology,{ddagger} La Jolla Institute for Molecular Medicine, San Diego, California; the Department of Medicine,* University of California, San Diego, San Diego, California; and the Department of Nutrition,{dagger} Division of Biological Sciences, Harvard School of Public Health, Boston, Massachusetts

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, hyperinsulinemia 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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