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

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Schilbach,  Leonhard
Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Sevgi, M., Rigoux, L., Kuehn, A. B., Mauer, J., Schilbach, L., Hess, M. E., et al. (2015). An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning. JOURNAL OF NEUROSCIENCE, 35(36), 12584-12592. doi:10.1523/JNEUROSCI.1589-15.2015.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0029-C300-0
Abstract
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.