Obesity is associated with increased cardiometabolic disease risk, although the vascular and metabolic features of obesity are often studied independently. Resistance to both insulin-mediated suppression of lipolysis and increases in microvascular blood flow are important risk factors for cardiometabolic diseases. Emerging evidence points to heightened NADPH oxidase (Nox) activity as a critical feature of reduced vascular and metabolic function. Overproduction of Nox-derived reactive oxygen species (ROS) is a major source of microvascular dysfunction in obesity and increased adipose tissue Nox activity is a main determinant of insulin resistance. In addition, Nox-derived ROS is an important component of increased lipolysis. However, the mechanistic basis for Nox in the intricate relationship between insulin control of vascular and metabolic responses is not well described. The overall objective of this study is to investigate whether increased Nox- derived ROS production in obesity impairs blood glucose profiles by reducing insulin-mediated suppression of lipolysis. We hypothesize that overproduction of Nox-derived ROS in people with obesity augments lipolysis and thereby impairs endothelial function and blood glucose profiles. To address this hypothesis, we will determine the mechanism(s) by which Nox increases lipolysis (Aim 1) and will determine if Nox-mediated increases in lipolysis impair endothelium-dependent vasodilation and blood glucose profiles by reducing the antilipolytic effect of insulin. (Aim 2). Our unique ability to combine microdialysis with hyperinsulinemic- euglycemic clamp techniques will establish molecular links between vascular and metabolic dysfunction. Enhancing the understanding of lipolysis control is impactful as obesity is characterized by elevated levels of plasma free fatty acids which, in turn, have negative consequences on vascular function and blood glucose control. This proposal is significant because it has the potential to offer new therapeutic targets directed at reducing the incidence of cardiometabolic diseases.