Cerebral insulin exerts anorexic effects in humans and animals. The underlying mechanisms, however, are not clear. Because insulin physiologically facilitates glucose uptake by most tissues of the body and thereby fosters intracellular energy supply, we hypothesized that intranasal insulin reduces food consumption via enhancement of the neuroenergetic level. In a double-blind, placebo–controlled, within-subject comparison, 15 healthy men (BMI 22.2 ± 0.37 kg/m2) aged 22–28 years were intranasally administered insulin (40 IU) or placebo after an overnight fast. Cerebral energy metabolism was assessed by 31P magnetic resonance spectroscopy. At 100 min after spray administration, participants consumed ad libitum from a test buffet. Our data show that intranasal insulin increases brain energy (i.e., adenosine triphosphate and phosphocreatine levels). Cerebral energy content correlates inversely with subsequent calorie intake in the control condition. Moreover, the neuroenergetic rise upon insulin administration correlates with the consecutive reduction in free-choice calorie consumption. Brain energy levels may therefore constitute a predictive value for food intake. Given that the brain synchronizes food intake behavior in dependence of its current energetic status, a future challenge in obesity treatment may be to therapeutically influence cerebral energy homeostasis. Intranasal insulin, after optimizing its application schema, seems a promising option in this regard.

Introduction: Cerebral insulin has an immediate lowering effect on hypothalamic-pituitary-adrenal (HPA) axis response to strong psychosocial stress. Objectives: So far, little is known about the modulation of ACTH and cortisol values by intranasal insulin administration under conditions of absolute rest as well as moderate activity changes. Aims: To determine whether single low-dose intranasal insulin application reduces the overall HPA-axis excitability and increases mood in healthy young men. Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 15 healthy young men (22 to 28 years old) received a single intranasal dose of 40 IU human insulin or placebo after an overnight fast. Mood as well as blood concentrations of cortisol and ACTH were measured before and after insulin administration. Results: In comparison to placebo, intranasal insulin reduces the HPA-axis excitability (all P > 0.004) as well as levels of arousal (P = 0.050), and increases feelings of well-being (P = 0.038) as well as of self-confidence (P = 0.005) as compared to placebo. Conclusions: Present study shows that single low-dose intranasal insulin application effectively improves mood and lowers the HPA-axis response to moderate activity changes in healthy young men. These findings have meaningful implications for humans who suffer from diseases characterized by enhanced stress axes activity such as depression and metabolic syndrome. Based on its diminishing effect on cortisol concentrations, intranasal insulin administration might represent a promising therapeutic strategy to prevent and to treat such diseases.