RT Journal Article SR Electronic T1 An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 12584 OP 12592 DO 10.1523/JNEUROSCI.1589-15.2015 VO 35 IS 36 A1 Sevgi, Meltem A1 Rigoux, Lionel A1 Kühn, Anne B. A1 Mauer, Jan A1 Schilbach, Leonhard A1 Hess, Martin E. A1 Gruendler, Theo O.J. A1 Ullsperger, Markus A1 Stephan, Klaas Enno A1 Brüning, Jens C. A1 Tittgemeyer, Marc YR 2015 UL http://www.jneurosci.org/content/35/36/12584.abstract AB Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction.SIGNIFICANCE STATEMENT Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity.