An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning

Sevgi M., Rigoux L., Kühn A.B., Mauer J., Schilbach L., Hess M.E., Gruendler T.O.J., Ullsperger M., Stephan K.E., Brüning J., & Tittgemeyer M.

Journal of Neuroscience. 35 (36) : 12584-12592

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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.