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NADPH oxidase (NOX) enzymes are one of the major superoxide-generating systems in cells. NOX-generated superoxide has been suggested to promote insulin resistance in the liver. However, the role of NOX enzymes in mediating metabolic dysfunction in other insulin target tissues remains unclear. Here, we show that NOX3 expression is induced in differentiated 3T3-L1 adipocytes upon treatment with proinflammatory cytokines. Superoxide production increased concurrently with NOX3 protein expression in cytokine-treated adipocytes, which was inhibited by the NOX inhibitor diphenyleneiodonium (DPI). Treatment of adipocytes with cytokines increased lipolysis and decreased PPARγ activity. Interestingly, treatment with DPI blunted lipolysis activation by cytokines but failed to restore PPARγ activity. siRNA-mediated NOX3 downregulation also prevented cytokine-induced superoxide generation and lipolysis. In line with increasing lipolysis, cytokines increased the phosphorylation of hormone-sensitive lipase (HSL), which was reversed by treatment with DPI and silencing of NOX3 expression. We conclude that NOX3 is a cytokine-inducible superoxide-generating enzyme in adipocytes, which promotes lipolysis through increasing phosphorylation of HSL. This suggests a key role for NOX3-mediated superoxide production in the increased adipocyte lipolysis in inflammatory settings.