Amyloid precursor protein (APP) has been characterized as an adipocyte-secreted protein that might contribute to obesity-related insulin resistance, inflammation, and dementia. In the current study, regulation of APP by the proinflammatory and insulin resistance-inducing cytokine tumor necrosis factor (TNF) alpha was determined in 3T3-L1 adipocytes. Interestingly, APP protein synthesis and mRNA expression were significantly increased by TNFalpha in a time-dependent manner with maximal induction observed after 24 h of treatment. Furthermore, TNFalpha induced APP mRNA expression dose-dependently with maximal 6.4-fold upregulation seen at 100 ng/ml effector. Moreover, inhibitor experiments suggested that TNFalpha-induced APP expression was mediated by nuclear factor kappa B. Taken together, we show for the first time a potent upregulation of APP by TNFalpha suggesting a potential role of this adipocyte-secreted protein in TNFalpha-induced insulin resistance and inflammatory disease.