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

• Published in: The Journal of neuroscience Vol. 35; no. 36; pp. 12584 - 12592
• Main Authors: Sevgi, Meltem, Rigoux, Lionel, Kuhn, Anne B, Mauer, Jan, Schilbach, Leonhard, Hess, Martin E, Gruendler, Theo OJ, Ullsperger, Markus, Stephan, Klaas Enno, Bruning, Jens C, Tittgemeyer, Marc
• Format: Journal Article
• Language: English
• Published: 09.09.2015
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.158915.2015

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.