PT  - JOURNAL ARTICLE
AU  - Sevgi, Meltem
AU  - Rigoux, Lionel
AU  - Kühn, Anne B.
AU  - Mauer, Jan
AU  - Schilbach, Leonhard
AU  - Hess, Martin E.
AU  - Gruendler, Theo O.J.
AU  - Ullsperger, Markus
AU  - Stephan, Klaas Enno
AU  - Brüning, Jens C.
AU  - Tittgemeyer, Marc
TI  - An Obesity-Predisposing Variant of the <em>FTO</em> Gene Regulates D2R-Dependent Reward Learning
AID  - 10.1523/JNEUROSCI.1589-15.2015
DP  - 2015 Sep 09
TA  - The Journal of Neuroscience
PG  - 12584--12592
VI  - 35
IP  - 36
4099  - http://www.jneurosci.org/content/35/36/12584.short
4100  - http://www.jneurosci.org/content/35/36/12584.full
SO  - J. Neurosci.2015 Sep 09; 35
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.