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Diabetologia. 2016 Dec;59(12):2622-2631. Epub 2016 Sep 6.

Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity.

Heni M1,2,3, Kullmann S4,5, Ahlqvist E6, Wagner R1,2,3, Machicao F2,3, Staiger H2,3,7,8, Häring HU1,2,3,8, Almgren P6, Groop LC6,9, Small DM10,11, Fritsche A1,2,3, Preissl H1,2,3,7,8,12.

Author information

1
Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
2
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Straße 47, 72076, Tübingen, Germany.
3
German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
4
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.
5
German Center for Diabetes Research (DZD e.V.), Tübingen, Germany. stephanie.kullmann@med.uni-tuebingen.de.
6
Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
7
Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls Universität Tübingen, Tübingen, Germany.
8
Interfaculty Centre for Pharmacogenomics and Pharma Research, Eberhard Karls University Tübingen, Tübingen, Germany.
9
Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
10
Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
11
The John B. Pierce Laboratory, New Haven, CT, USA.
12
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.

Abstract

AIMS/HYPOTHESIS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS/INTERPRETATION:

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.

KEYWORDS:

ANKK1; Body fat; Dopamine; FTO; Insulin sensitivity; TaqIA

PMID:
27600277
DOI:
10.1007/s00125-016-4095-0
[Indexed for MEDLINE]

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