Using novel mice with conditional NOX2 deletion, this manuscript raises the possibility that the pro-inflammatory, detrimental consequences of NADPH oxidase activation in macrophages can be pharmacologically separated from physiologic NADPH oxidase-based signaling in other key cells such as neurons and adipocytes, suggesting that targeted NOX2-based therapies could preserve physiologic function in the context of obesity. The gene discussed is CYBB; the disease is obesity due to melanocortin 4 receptor deficiency.