An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning.
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.
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
Meltem
http://orcid.org/0000-0002-6874-0668
M
Sevgi
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
Lionel
http://orcid.org/0000-0003-3761-8931
L
Rigoux
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, 50931 Cologne, Germany.
Anne B
AB
Kühn
Weill Cornell Medical College, Department of Pharmacology, New York, New York 10021.
Jan
J
Mauer
Department of Psychiatry, University Hospital of Cologne, 50937 Cologne, Germany, Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
Leonhard
L
Schilbach
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.
Martin E
ME
Hess
Department of Psychiatry, University Hospital of Cologne, 50937 Cologne, Germany, Economics, Otto-von-Guericke-University Magdeburg, 39106 Magdeburg, Germany, Center for Behavioral Brain Sciences, 39106 Magdeburg, Germany.
Theo O J
TO
Gruendler
Departments of Neuropsychology and Center for Behavioral Brain Sciences, 39106 Magdeburg, Germany, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, 6525EZ Nijmegen, The Netherlands.
Markus
M
Ullsperger
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany, Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and Swiss Federal Institute of Technology, 8032 Zurich, Switzerland, Wellcome Trust Centre for Neuroimaging, University College London, London WC1N 3BG, United Kingdom, and.
Klaas Enno
KE
Stephan
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine, University Hospital of Cologne, 50931 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, 50931 Cologne, Germany tittgemeyer@sf.mpg.de bruening@sf.mpg.de.
Jens C
JC
Brüning
Max Planck Institute for Metabolism Research, 50931 Cologne, Germany, tittgemeyer@sf.mpg.de bruening@sf.mpg.de.
Marc
http://orcid.org/0000-0001-5072-2149
M
Tittgemeyer
D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D063132:Connectome; D005260:Female; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012201:Reward
D011506:Proteins; D017448:Receptors, Dopamine D2; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases
dopamine; fMRI; genetics; modeling; obesity; reinforcement learning