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

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.

DRD2: Bridging the Genome and Ingestive Behavior

“…More specifically, in a sample of 2245 individuals the FTO SNP rs 805136 only influenced body fat content, waist-to-hip ratio, insulin sensitivity and fasting insulin if they also carried the at-risk allele of the ANKK1 SNP [141]. Strikingly, a similar effect was observed with insulin action in the DRD2 rich caudate nucleus: FTO influenced insulin sensitivity only in A1 allele carriers.…”

“…First, variations in the fat mass and obesity-associated (FTO) gene are the strongest polygenic determinants of adiposity [32] and inactivation of this gene impairs DRD2-dependent neurotransmission and function in rodents [33] and DRD2-dependent learning in humans [34]. Second, the TaqIA RFLP, which is associated with variation in DRD2 receptor density [35–38], was recently shown to interact with an FTO gene variant to influence adiposity, central and peripheral insulin resistance and DRD2-dependent learning [34, 39]. In both studies the influence of FTO on these phenotypes was found to be either greater in individuals who also possessed a copy of the TaqIA at-risk allele or dependent upon individuals also having this genotype.…”

What Twin Studies Tell Us About Brain Responses to Food Cues

“…Individuals carrying risk alleles are at risk of weight gain related to hypo-responsivity to food cues or taste receipt within dorsal striatal regions (caudate) [85, 86], whereas in non-carriers, hyper-responsivity promotes obesity risk. While the interpretation of such findings as a deficit in experienced reward has been debated [87, 88], inherited variability in dopamine-dependent neural signaling clearly influences components of CNS appetite regulation and obesity risk directly [89, 8, 90] and via interactions with other risk genes [84, 91]. …”

“…Moreover, each individual inherits a blend of risk and protective alleles, which could also increase variability within samples enrolled in single-gene association studies. Moreover, these studies might also be misleading when genetic effects are modified by other inherited factors [84, 91], sex, BMI [82, 81], or the particular loci under investigation [92]. Finally, normal weight adults with high-risk genotypes may have neural responsiveness that differs from high-risk allele carriers who are vulnerable to weight gain, and some results are derived from exclusively normal weight samples [93, 82, 84].…”

Role of RNA modifications in brain and behavior

“…112 Other studies have shown association between FTO and ANKK1 variants with decreased D2 receptor density in the nucleus accumbens. 113 …”