AbstractContextBehaviorally, the most pronounced effects of leptin substitution in leptin deficiency are the hunger-decreasing and postprandial satiety-prolonging effects of the adipokine. Previously, with functional magnetic resonance imaging (MRI), we and others showed that eating behavior–controlling effects are at least in part conveyed by the reward system. However, to date, it is unclear if leptin only modulates eating behavior specific brain reward action or if it also alters the reward function of the brain unrelated to eating behavior.ObjectiveWe investigated with functional MRI the effects of metreleptin on the reward system in a reward task unrelated to eating behavior, the monetary incentive delay task.DesignMeasurements in 4 patients with the very rare disease of lipodystrophy (LD), resulting in leptin deficiency, and 3 untreated healthy control persons were performed at 4 different time points: before start and over 12 weeks of metreleptin treatment. Inside the MRI scanner, participants performed the monetary incentive delay task and brain activity during the reward receipt phase of the trial was analyzed.ResultsWe found a reward-related brain activity decrease in our 4 patients with LD over the 12 weeks of metreleptin treatment in the subgenual region, a brain area associated with the reward network, which was not observed in our 3 untreated healthy control persons.ConclusionsThese results suggest that leptin replacement in LD induces changes of brain activity during reward reception processing completely unrelated to eating behavior or food stimuli. This could suggest eating behavior-unrelated functions of leptin in the human reward system.Trial registrationThe trial is registered as trial No. 147/10-ek at the ethics committee of the University of Leipzig and at the State Directorate of Saxony (Landesdirektion Sachsen).