Although tumor necrosis factor-α (TNF-α) 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-α remain elusive. We hypothesized that autoamplification of TNF-α contributes to the maintenance of elevated TNF-α in obesity. Treatment of 3T3-L1 adipocytes with TNF-α, or injection of TNF-α into C57BL/6J mice, up-regulated TNF-α mRNA in adipocytes and in adipose tissues, respectively. Ob/ob male but not female mice lacking TNF-α receptors showed significantly lower levels of adipose TNF-α mRNA when compared with TNF-α receptor-expressing ob/ob mice. Thus, the lack of endogenous TNF-α signaling reduced adipose TNF-α mRNA in ob/ob male mice. Additionally, hyperinsulinemia potentiated this TNF-α-mediated autoamplification response in adipose tissues and in adipocytes in a synergistic and dose-dependent manner. Studies in which TNF-α was injected into lean mice lacking individual TNF-α receptors indicated that TNF-α autoamplification in adipose tissues was mediated primarily via the p55 TNF-α receptor whereas the p75 TNF-α receptor appeared to augment this response. Finally, TNF-α autoamplification in adipocytes occurred via the protein kinase C signaling pathway and the transcription factor nuclear factor-κB. Thus, TNF-α can positively autoregulate its own biosynthesis in adipose tissue, contributing to the maintenance of elevated TNF-α in obesity.