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Running headHigh-fat high-sugar diet relates to central dopamine in humans *Authors contributed equally to the study. of 1 43We thank Arno Villringer and his coworkers of the Department of Neurology (MaxPlanck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany) for providing lab space and additional resources. We further thank SusePrejawa for administrative support, Ramona Menger and Sylvia Stasch for preparing the intervention, and Bettina Johst and Steven Kalinke for cognitive task programming. Furthermore we thank Emmy Kaspar for participating in the preparation of the study, Lisa Ulbrich, Pauline Baßler, and Denise Linke for testing participants. Special thanks to Mathis Lammert, Linda Grasser, Lisa Leyendecker, Franziska Schwachheim for performing the blood drawings and physiological measurements. We thank Lydia Hellrung for helpful input regarding the APTD procedure. The authors have stated explicitly that there are no conflicts of interest in connection with this article. Performed experiments, analyzed data and co-wrote the paper. L.K.P.; Designed and performed experiments, analyzed data and provided feedback for the paper. L.K.J.;Designed experiments, analyzed data and co-wrote the paper. S.H.; developed the lowprotein diet plan for successful intervention. U.C.; coordinated and supervised the analyses of amino acids and metabolic parameters. A.H.; supervised the research, conceived the original idea, designed experiments, helped interpreting data and provided feedback for the paper. of 2 43 AbstractObesity is associated with alterations in dopaminergic transmission and cognitive function. Recent findings from rodent studies suggest that diets rich in saturated fat and refined sugars (HFS) induce changes in the dopamine system independent of excessive body weight. However, so far the impact of HFS on the human brain has not been investigated. Here, we compared the effect of dietary dopamine depletion on dopamine dependent cognitive tasks between two groups that differ in habitual intake of dietary fat and sugar. Specifically, we used a double-blind within-subject crossover design to compare the effect of acute phenylalanine/tyrosine depletion (APTD) on a reinforcement learning and a working memory task, in two groups that are on opposite ends of the spectrum of self-reported HFS intake (low vs. high intake: LFS vs. HFS group). We tested 31 healthy young women, who were matched for BMI (mostly normal weight to overweight) and IQ. Depletion of central dopamine reduced the working memory specific performance on the operation span task (OSPAN) in the LFS, but not in the HFS group (p = 0.023, r = 0.210). Learning from positive and negative reinforcement (probabilistic selection task: PST) was increased in both diet groups after dopamine depletion (p = 0.048, r = 0.144). As secondary exploratory research question we measured peripheral dopamine precursor availability (pDAP) at baseline as an estimate for central dopamine levels. The HFS group had a significantly higher pDAP at baseline compared...