Hypothalamic reactive oxygen species are required for insulin-induced food intake inhibition. A NADPH oxidase-dependent mechanism.

Abstract

Objective: Insulin plays an important role in the hypothalamic control of energy balance, especially by reducing food intake. Emerging data points out a pivotal role of reactive oxygen species (ROS) in the energy homeostasis regulation, but their involvement in the anorexigenic effect of insulin is unknown. Furthermore, ROS signal derived from NADPH oxidase activation is required for physiological insulin effects in peripheral cells. In this study, we investigated the involvement of hypothalamic ROS and NADPH oxidase in the feeding behavior regulation by insulin.

Research design and methods: We first measured hypothalamic ROS level and food intake after acute intracerebroventricular (icv) injection of insulin. Second, effect of a pretreatment with a ROS scavenger or a NADPH oxidase inhibitor was evaluated. Third, we examined the consequences of two nutritional conditions of central insulin unresponsiveness (fasting or short-term high-fat diet) on the insulin ability to modify ROS level and food intake.

Results: In normal chow-fed mice, insulin inhibited food intake. At the same dose, insulin rapidly and transiently increased hypothalamic ROS level by 36 %. The pharmacological suppression of this insulin-stimulated ROS elevation, either by antioxidant or by a NADPH oxidase inhibitor abolished the anorexigenic effect of insulin. Finally, in fasted- and short-term high-fat diet-fed mice insulin did not promote any more elevation of ROS level and food intake inhibition, likely due to higher hypothalamic diet-induced antioxidant defence system.

Conclusions: A Hypothalamic ROS increase through NADPH oxidase is required for the anorexigenic effect of insulin.