This study investigates the role of increased oxidative stress in accumulated fat as a pathogenic mechanism of obesity-associated metabolic syndrome. The authors found that fat accumulation is associated with systemic oxidative stress in both humans and mice, with elevated levels of lipid peroxidation and markers of oxidative injury correlating with BMI and waist circumference. In obese mice, production of reactive oxygen species (ROS) increased selectively in adipose tissue, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidant enzymes. In cultured adipocytes, elevated levels of fatty acids increased ROS production via NADPH oxidase activation, leading to dysregulated production of adipocytokines such as adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Treatment with a NADPH oxidase inhibitor in obese mice reduced ROS production in adipose tissue, improved diabetes, hyperlipidemia, and hepatic steatosis, and restored the dysregulation of adipocytokines. These findings suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that targeting the redox state in adipose tissue could be a potential therapeutic approach for obesity-associated metabolic syndrome.This study investigates the role of increased oxidative stress in accumulated fat as a pathogenic mechanism of obesity-associated metabolic syndrome. The authors found that fat accumulation is associated with systemic oxidative stress in both humans and mice, with elevated levels of lipid peroxidation and markers of oxidative injury correlating with BMI and waist circumference. In obese mice, production of reactive oxygen species (ROS) increased selectively in adipose tissue, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidant enzymes. In cultured adipocytes, elevated levels of fatty acids increased ROS production via NADPH oxidase activation, leading to dysregulated production of adipocytokines such as adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Treatment with a NADPH oxidase inhibitor in obese mice reduced ROS production in adipose tissue, improved diabetes, hyperlipidemia, and hepatic steatosis, and restored the dysregulation of adipocytokines. These findings suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that targeting the redox state in adipose tissue could be a potential therapeutic approach for obesity-associated metabolic syndrome.