Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity.
Variations in FTO are the strongest common genetic determinants of adiposity, and may partly act by influencing dopaminergic signalling in the brain leading to altered reward processing that promotes increased food intake. Therefore, we investigated the impact of such an interaction on body composition, and peripheral and brain insulin sensitivity.



Participants from the Tübingen Family study (n = 2245) and the Malmö Diet and Cancer study (n = 2921) were genotyped for FTO SNP rs8050136 and ANKK1 SNP rs1800497. Insulin sensitivity in the caudate nucleus, an important reward area in the brain, was assessed by fMRI in 45 participants combined with intranasal insulin administration.



We found evidence of an interaction between variations in FTO and an ANKK1 polymorphism that associates with dopamine (D2) receptor density. In cases of reduced D2 receptor availability, as indicated by the ANKK1 polymorphism, FTO variation was associated with increased body fat and waist circumference and reduced peripheral insulin sensitivity. Similarly, altered central insulin sensitivity was observed in the caudate nucleus in individuals with the FTO obesity-risk allele and diminished D2 receptors.



The effects of variations in FTO are dependent on dopamine D2 receptor density (determined by the ANKK1 polymorphism). Carriers of both risk alleles might, therefore, be at increased risk of obesity and diabetes.
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
Martin
M
Heni
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany. stephanie.kullmann@med.uni-tuebingen.de.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany. stephanie.kullmann@med.uni-tuebingen.de.
Stephanie
S
Kullmann
Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Emma
E
Ahlqvist
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
Robert
R
Wagner
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
Fausto
F
Machicao
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.|Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.
Harald
H
Staiger
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.|Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.
Hans-Ulrich
HU
Häring
Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
Peter
P
Almgren
Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.|Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Leif C
LC
Groop
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|The John B. Pierce Laboratory, New Haven, CT, USA.
Dana M
DM
Small
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
Andreas
A
Fritsche
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.|German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.|Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, Germany.|Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.|Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Hubert
H
Preissl
D000273:Adipose Tissue / Q000378:metabolism; D000281:Administration, Intranasal; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000008:administration & dosage; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*
C581293:DRD2 protein, human; D007328:Insulin; D017448:Receptors, Dopamine D2; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases
ANKK1; Body fat; Dopamine; FTO; Insulin sensitivity; TaqIA