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

Sevgi, Meltem; Rigoux, Lionel; Kuhn, Anne; Mauer, Jan; Schilbach, Leonhard; Hess, Martin W.; Gruendler, Theo O.J.; Ullsperger, Markus; Stephan, Klaas Ε.; Brüning, Jens C.; Tittgemeyer, Marc

doi:10.1523/jneurosci.1589-15.2015

Cited by 82 publications

(84 citation statements)

References 60 publications

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“…Impaired brain insulin signalling could therefore contribute to increased body fat content and increased waist circumference, as well as to reduced peripheral insulin sensitivity in carriers of both risk alleles. In addition, our results in combination with the finding of an altered midbrain response in participants carrying both polymorphisms during a reward learning task [42] indicate that the interaction of FTO and ANNK1 affects metabolic and behavioural brain networks.…”

Section: Discussionsupporting

confidence: 65%

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

et al. 2016

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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.

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Section: Discussionsupporting

confidence: 65%

“…Specifically, an attenuated response to food in the striatum of risk-allele carriers was a predictor of further weight gain [41]. A recent study in humans identified an interaction between FTO and ANNK1 polymorphisms that determines midbrain activity during reward learning [42].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…It is worth noting, however, that even within the cohorts of adults tested previously, there is little consistency in reported effects across studies. Moreover, with one exception (14), none of the prior work links FTO genotypic differences to neural differences in canonical reward regions despite the fact that previous studies have demonstrated a causal role of FTO in regulating dopaminergic transmission (12) and also in modulating mesocorticolimbic circuitry in adults (13). The effects reported here in children in ventral striatum function and structure, as well as the voxel-wise whole-brain exploratory analysis, constrain the FTO genotypic differences to canonical reward neurocircuitry.…”

Section: Discussionmentioning

confidence: 59%

“…Although the FTO gene is highly expressed in the brain (1), the mechanism by which this gene promotes unhealthy eating behaviors remains poorly understood. Previous studies have suggested that FTO alters dopaminergic midbrain circuitry (12,13). Thus, one possibility is that the FTO gene influences the early development and responsivity of reward-related brain structures, thereby predisposing individuals to develop patterns of unhealthy eating.…”

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confidence: 99%

Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues

Rapuano

Zieselman

Kelley

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is a major public health concern that involves an interaction between genetic susceptibility and exposure to environmental cues (e.g., food marketing); however, the mechanisms that link these factors and contribute to unhealthy eating are unclear. Using a well-known obesity risk polymorphism (FTO rs9939609) in a sample of 78 children (ages 9-12 y), we observed that children at risk for obesity exhibited stronger responses to food commercials in the nucleus accumbens (NAcc) than children not at risk. Similarly, children at a higher genetic risk for obesity demonstrated larger NAcc volumes. Although a recessive model of this polymorphism best predicted body mass and adiposity, a dominant model was most predictive of NAcc size and responsivity to food cues. These findings suggest that children genetically at risk for obesity are predisposed to represent reward signals more strongly, which, in turn, may contribute to unhealthy eating behaviors later in life.T he relationship between genes and sensitivity to environmental cues is elusive, yet it is paramount to understanding the development of potentially maladaptive human behaviors. The rising prevalence of obesity is a major public health concern that has been attributed to various factors, such as genetic susceptibility (1), and increases in the availability and marketing of calorie-dense foods (2). However, little is known about how genetic predisposition to obesity influences sensitivity to real-world food cues and contributes to the development of unhealthy eating behaviors.Previous neuroimaging studies have demonstrated that responses to food cues in reward-related regions of the brain, such as the nucleus accumbens (NAcc), predict weight gain in adulthood (3) and giving in to food temptations in daily life (4). Furthermore, structural differences in NAcc volume have been positively associated with body mass index (BMI) in adults (5, 6). Because the development of the NAcc precedes the development of prefrontal control systems (7), this structure is suggested to play a key role in motivating and establishing unhealthy eating behaviors early in the lifespan. Importantly, genetic factors are a known contributor to brain development (8) and may influence risky behaviors during childhood and adolescence by biasing the early development of anatomical structures underlying reward-related brain function.In addition, the notion that genes contribute to obesity has recently gained much attention. More specifically, the fat-mass and obesity-associated (FTO) rs9939609 polymorphism has been strongly related to increased BMI and adiposity across the lifespan, and is suggested to influence food intake and food choice, rather than energy expenditure (9-11). Those with two high-risk "A" alleles (AA) are at an enhanced risk for obesity compared with those with two low-risk "T" alleles (TT) or those who are heterozygous (AT) for the FTO rs9939609 polymorphism. Although the FTO gene is highly expressed in the brain (1), the mechanism by which this gene promotes unhealthy...

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“…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.…”

Section: Why Drd2?mentioning

confidence: 99%

DRD2: Bridging the Genome and Ingestive Behavior

Sun

Luquet

2017

Trends in Cognitive Sciences

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Recent work highlights the importance of genetic variants that influence brain structure and function in conferring risk for polygenic obesity. The neurotransmitter dopamine (DA) plays a pivotal role in energy balance by integrating metabolic signals with circuits supporting cognitive, perceptual and appetitive functions that guide feeding. It has also been established that diet and obesity alter DA signaling leading to compulsive-like feeding and neurocognitive impairments. This raises the possibility that genetic variants that influence DA signaling and adaptation confer risk for overeating and cognitive decline. We consider the role of two common gene variants, FTO and TaqIA rs1800497 in driving gene * environment interactions promoting obesity, metabolic dysfunction, and cognitive change via their influence on dopamine receptor subtype 2 signaling.

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

Cited by 82 publications

References 60 publications

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

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

Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues

DRD2: Bridging the Genome and Ingestive Behavior

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