scispace - formally typeset
Search or ask a question
Journal ArticleDOI

An obesity-associated risk allele within the FTO gene affects human brain activity for areas important for emotion, impulse control and reward in response to food images.

TL;DR: The results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.
Abstract: Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (fMRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie food while brain activity was measured via fMRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype (AA) had increased activity compared with the non-risk (TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing.

Summary (4 min read)

INTRODUCTION

  • Several different FTO single nucleotide polymorphisms (SNPs) are associated with a higher body mass index (BMI) (Sällman Almén et al., 2013; Scuteri et al., 2007a) , and higher energy intake (Speakman, 2013) .
  • Moreover, experiments in rodents show that changes in FTO expression levels in the hypothalamus affect feeding behavior (Frederiksen, Skakkebaek, & Andersson, 2007; Olszewski et al., 2009; Tung et al., 2010) .
  • Personality scales for the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS), which measure punishment and reward sensitivity respectively, are two such tools which correlate with inactivity and poor diet (Carver & White, 1994; Dietrich, Federbusch, Grellmann, Villringer, & Horstmann, 2014; Meule, 2013; Voigt et al., 2009) .

FTO Associated Brain Activity 5

  • To date, however, few fMRI studies have examined how genetic profile is associated with brain responses to food in obesity.
  • A recent study found that people with the FTO risk allele for rs8050136 had reduced activity in the right prefrontal cortex while viewing food images in a postprandial state, but not while fasting (Heni et al., 2014) .
  • Notably, their cohort of participants had a normal BMI with no obese participants.
  • Against this background, the authors explore for the first time the association between FTO genotype, BMI, and neural responses to food images of either low-or high-calorie content.

Participants

  • Prior to any experimental procedures, all participants gave written informed consent to the study which conformed to the Declaration of Helsinki and approved by the local ethics committee.
  • Genotyping of the FTO single nucleotide polymorphism (SNP) rs9939609 was performed with a pre-designed Taqman single-nucleotide polymorphism genotyping assay (Applied Biosystems, Foster City, USA) and an ABI7900 genetic analyzer with SDS 2.2 software at the Uppsala Genome Center (http://www.genpat.uu.se/node462).
  • Only homozygous participants were included in the study.
  • Hunger ratings were also assessed on a 1-10 scale with higher numbers indicating greater feelings of hunger.

Behavioral Questionnaires

  • Clinical measures for punishment sensitivity and reward-seeking behavior were acquired using the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) questionnaires (Carver & White, 1994) .
  • Each item was represented by a statement, where the participant indicated how much s/he agreed or FTO Associated Brain Activity 7 disagreed on a four-point scale.
  • The BIS included only one scale, evaluating the reactions to the anticipation of punishment and anxiety, while the BAS included three subscales: Drive, which represents the pursuit of desired goals; Fun Seeking, which evaluates the desire for new rewards and impulsivity; and Reward Responsiveness, which focuses on positive reactions anticipating rewards.

Preprocessing of fMRI data

  • All preprocessing steps were performed using software package Statistical Parametric Mapping (SPM, version 8, http://www.fil.ion.ucl.ac.uk/spm/), implemented in MATLAB (version R2014a, 11 FEB 2014 .
  • The images were realigned and estimated to remove movement artefacts in the data.
  • EPI images were further matched with the structural image using coregistration.
  • The anatomical image was segmented to strip away unnecessary tissue in the images.
  • Tissue probability maps were introduced in the segmentation step to differentiate between gray matter, white matter and cerebrospinal fluid in each individual.

Statistical Analysis

  • All fMRI statistical analysis was performed using the same versions of SPM and MATLAB listed in preprocessing steps.
  • For all whole-brain results, a family wise error FTO Associated Brain Activity 9 (FWE) corrected significance level was set at p < 0.05 to correct for multiple testing.
  • This contrast was then tested using a between-groups t-test followed by directional post-hoc comparisons as well as with a multiple regression analysis testing for interactions between genotype and BMI, BIS, or BAS individually.
  • Bilateral masks of such areas were produced using the Wake Forest University Pickatlas toolbox (Maldjian, Laurienti, Kraft, & Burdette, 2003) within SPM.
  • Results for the PCA were considered significant if the percentage of inertia summing from the two largest eigenvalues exceeded values listed in a significance table based on 10,000 analyses with similar numbers of individuals and independent variables (Lê et al., 2008) .

RESULTS

  • The obesity-associated FTO SNP rs9939609, is associated with increased activity in response to food images.
  • BOLD signals were measured as participants were shown images of low-calorie (LC) food, high-calorie (HC) food, or control images in a block design format.
  • Areas included the posterior cingulate cortex (PCC), cingulate gyrus, cuneus, and precuneus (Table 2 ).
  • A multiple regression analysis found an interaction between genotype and BMI, post-hoc comparisons found significant clusters for the AA genotype while BMI was decreasing in the PCC, cingulate gyrus, middle occipital gyrus, and precuneus (Supplementary Table 1 ).
  • Within the t-test comparison between genotypes, a significant cluster showing greater activity in the AA genotype was FTO Associated Brain Activity 11 found in the putamen after performing a small-volumes correction using a 6 mmradius sphere over the lowest FWE-corrected p-value in the cluster (Table 2 ).

Differential patterns of behavior for each FTO genotype depending on body-mass index.

  • The authors next tested if behavioral questionaires corrobarated the findings from the imaging experiments.
  • The authors then performed a principle component analysis within each genotype using the BIS and the three BAS subscales (Drive, Fun Seeking, and Reward Responsiveness) as variables of interest with BMI as a quantitative supplementary variable.
  • For both analyses, all the variables of interest were well projected and the first two dimensions accounted for ≈80% of the variablity (considered significant based on critera listed in methods under statistical analysis subheading, 81.4 > 80.0 for the AA group and 79.2 > 76.5 in the TT group).
  • Moreover, the variables of interest projected to the same quandrants except for the Drive and Fun Seeking subscales, which were switched between the two different genotypes.
  • Furthermore, the authors followed up the association between the BIS and BMI using a multiple regression analysis testing if BIS scores could be predicted by genotype, BMI, or their interaction.

DISCUSSION

  • The authors examined whether an obesity-associated genotype affects the neural processing of food images with different caloric content and to what extent body-mass index (BMI) is an important factor.
  • The authors found the AA genotype had increased brain activity compared to the TT genotype when viewing food images with different caloric contents, specifically in areas important for emotion (cingulate gyrus), memory, and self-image (cuneus and precuneus) and reward .
  • Thus, discrimination between HC and LC foods may be handled differently for each genotype depending on BMI.
  • Next, the authors corroborate their findings in the imaging study with personality questionnaires examining behavioral characteristics related to impulsivity and rewardprocessing: namely the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) scales.
  • The authors found that the BIS as well as subscales of the BAS correlated with BMI oppositely in each genotype.

FTO Associated Brain Activity 14

  • In between-groups comparisons, as well as multiple regression analysis, the authors found significant clusters of brain activity when testing a contrast for caloric discrimination (HC food images opposed to LC food images).
  • Specifically, the authors found increased neural activation in the AA genotype compared to the TT genotype within the posterior cingulate cortex (PCC), cingulate gyrus, cuneus and precuneus.
  • The PCC is a well-connected and multifunctional brain area associated with emotional processing, and a central node in the default mode network (DMN): involved in arousal/awareness, balancing external and internal thought, and emotion (Leech & Sharp, 2014) .
  • Thus, the AA genotype in their cohort confirms previous reports equating impulsivity with obesity/overeating (Meule, 2013) specifically in one study which also found a negative correlation between BIS and BMI in males (Dietrich et al., 2014) .
  • In conclusion, their findings offer insight into the relationship between FTO, obesity, and brain activity; and suggest that overweight/obese populations have different attitudes and functional processing for food images depending on genetic background.

B)

  • A region of interest analysis found a significant cluster within the putamen after a smallvolumes correction.
  • The BIS evaluates inhibitory behavior in the anticipation of punishment and anxiety, while the BAS included three subscales: Drive, which represents the pursuit of desired goals; Fun Seeking, which evaluates the desire for new rewards and impulsivity; and Reward Responsiveness, which focuses on positive reactions anticipating rewards.
  • The behavioral variables were all well projected in each group.
  • A) variables factor map for the AA genotype.
  • BMI was positively correlated with BIS and negatively correlated with the BAS Fun Seeking subscale.

Did you find this useful? Give us your feedback

Content maybe subject to copyright    Report

Wiemerslage, L, Nilsson, EK, Solstrand Dahlberg, L, Ence-Eriksson, F, Castillo,
S, Larsen, AL, Bylund, SBA, Hogenkamp, PS, Olivo, G, Bandstein, M, Titova,
OE, Larsson, E-M, Benedict, C, Brooks, SJ and Schiöth, HB
An obesity-associated risk allele within the FTO gene affects human brain
activity for areas important for emotion, impulse control and reward in
response to food images.
http://researchonline.ljmu.ac.uk/id/eprint/9287/
Article
LJMU has developed LJMU Research Online for users to access the research output of the
University more effectively. Copyright © and Moral Rights for the papers on this site are retained by
the individual authors and/or other copyright owners. Users may download and/or print one copy of
any article(s) in LJMU Research Online to facilitate their private study or for non-commercial research.
You may not engage in further distribution of the material or use it for any profit-making activities or
any commercial gain.
The version presented here may differ from the published version or from the version of the record.
Please see the repository URL above for details on accessing the published version and note that
access may require a subscription.
For more information please contact researchonline@ljmu.ac.uk
http://researchonline.ljmu.ac.uk/
Citation (please note it is advisable to refer to the publisher’s version if you
intend to cite from this work)
Wiemerslage, L, Nilsson, EK, Solstrand Dahlberg, L, Ence-Eriksson, F,
Castillo, S, Larsen, AL, Bylund, SBA, Hogenkamp, PS, Olivo, G, Bandstein,
M, Titova, OE, Larsson, E-M, Benedict, C, Brooks, SJ and Schiöth, HB (2016)
An obesity-associated risk allele within the FTO gene affects human brain
LJMU Research Online

http://researchonline.ljmu.ac.uk/

FTO Associated Brain Activity 1
Title 1
An obesity-associated risk allele within the FTO gene affects brain activity for areas 2
important for emotion, impulse control, and reward in response to food images. 3
4
Running Title 5
FTO Associated Brain Activity 6
7
Author names and affiliation 8
Lyle Wiemerslage*
§
, Emil K Nilsson
§
, Linda Solstrand Dahlberg
§
, Fia Ence-Eriksson
§
, 9
Sandra Castillo
§
, Anna L Larsen
§
, Simon BA Bylund
§
, Pleunie S Hogenkamp
§
, Gaia 10
Olivo
§
, Marcus Bandstein
§
, Olga E Titova
§
, Elna-Marie Larsson
, Christian Benedict
§
, 11
Samantha J Brooks
, Helgi B Schiöth
§
12
13
Uppsala University § 14
Department of Neuroscience, Functional Pharmacology 15
Biomedicinska Centrum (BMC) 16
Husargatan 3, Box 593 17
751 24 Uppsala, Sweden 18
19
Section of Neuroradiology 20
Department of Radiology, Uppsala University 21
Akademiska Sjukhuset 22
751 85 Uppsala, Sweden 23
24
University of Cape Town 25
Department of Psychiatry 26
Old Groote Schuur Hospital 27
J2 Building 28
Anzio Road 29
Observatory, Cape Town, South Africa. 30
31
Corresponding author 32
Uppsala University * 33
Department of Neuroscience, Functional Pharmacology 34
Biomedicinska Centrum (BMC) 35

FTO Associated Brain Activity 2
Husargatan 3, Box 593 36
751 24 Uppsala, Sweden 37
lyle.wiemerslage@neuro.uu.se 38
39
Number of: 40
Figures = 3 41
Tables = 1 42
Words: 43
o Abstract = 197 44
o Introduction = 565 45
o Entire Manuscript (excluding references and figure legends) = 3,972 46
47
Keywords: 48
FTO, fMRI, SNP, obesity, food 49
50
Conflict of Interest: 51
The authors declare no conflicts of interest. 52

FTO Associated Brain Activity 3
ABSTRACT 53
Understanding how genetics influences obesity, brain activity, and eating behavior will 54
add important insight for developing strategies for weight-loss treatment, as obesity may stem 55
from different causes and as individual feeding behavior may depend on genetic differences. 56
To this end, we examined how an obesity risk-allele for the FTO gene affects brain activity in 57
response to food images of different caloric content via fMRI. 30 participants homozygous 58
for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie 59
food while brain activity was measured via fMRI. In a whole-brain analysis, we found that 60
people with the FTO risk-allele genotype (AA) had increased activity than the non-risk (TT) 61
genotype in the posterior cingulate, cuneus, precuneus, and putamen. Moreover, higher BMI 62
in the AA genotype was associated with reduced activity to food images in areas important for 63
emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and 64
lentiform nucleus). Lastly, we corroborate our findings with behavioral scales for the 65
behavioral inhibition and activation systems (BIS/BAS). Our results suggest that the two 66
genotypes are associated with differential neural processing of food images, which may 67
influence weight status through diminished impulse control and reward processing. 68
69
Keywords: 70
fMRI, FTO, SNP, BMI, food images, obesity 71

Citations
More filters
Journal ArticleDOI
TL;DR: The most prominent factors associated with brain insulin resistance are elaborate, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences.
Abstract: Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

349 citations


Cites background from "An obesity-associated risk allele w..."

  • ...Also functionally, the FTO risk allele affects brain areas important for reward processing and food-cue reactivity (215, 263, 389)....

    [...]

Journal ArticleDOI
TL;DR: The synthesis of the latest evidence consolidates conclusions drawn in the initial systematic review that BED represents a distinct phenotype within the obesity spectrum that is characterized by increased impulsivity.
Abstract: The specific eating pattern of Binge Eating Disorder (BED) patients has provoked the assumption that BED might represent a phenotype within the obesity spectrum that is characterized by increased impulsivity. Following the guidelines of the PRISMA statement (preferred reporting items for systematic reviews and meta-analyses), we here provide a systematic update on the evidence on food-related impulsivity in obese individuals, with and without BED, as well as normal-weight individuals. We separately analyzed potential group differences in the impulsivity components of reward sensitivity and rash-spontaneous behavior. Our search resulted in twenty experimental studies with high methodological quality. The synthesis of the latest evidence consolidates conclusions drawn in our initial systematic review that BED represents a distinct phenotype within the obesity spectrum that is characterized by increased impulsivity. Rash-spontaneous behavior in general, and specifically towards food, is increased in BED, while food-specific reward sensitivity is also increased in obese individuals without BED, but potentially to a lesser degree. A major next step for research entails the investigation of sub-domains and temporal components of inhibitory control in BED and obesity. Based on the evidence of impaired inhibitory control in BED, affected patients might profit from interventions that address impulsive behavior.

195 citations

Journal ArticleDOI
TL;DR: It is shown that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment and this results suggest FTO plays important roles in neurogenesis, as well as in learning and memory.
Abstract: Fat mass and obesity-associated gene (FTO) is a member of the Fe (II)- and oxoglutarate-dependent AlkB dioxygenase family and is linked to both obesity and intellectual disability. The role of FTO in neurodevelopment and neurogenesis, however, remains largely unknown. Here we show that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to decreased brain size and body weight. We find that FTO deficiency could reduce the proliferation and neuronal differentiation of adult neural stem cells in vivo, which leads to impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we went on to perform genome-wide m6A profiling and observed dynamic m6A modification during postnatal neurodevelopment. The loss of FTO led to the altered expression of several key components of the brain derived neurotrophic factor pathway that were marked by m6A. These results together suggest FTO plays important roles in neurogenesis, as well as in learning and memory.

194 citations

Journal ArticleDOI
TL;DR: It is shown that children genetically at risk for obesity exhibit stronger reward-related responses to real-world food cues in the nucleus accumbens, a brain area canonically associated with reward processing, which may contribute to unhealthy eating behaviors later in life.
Abstract: 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.

76 citations

Journal ArticleDOI
TL;DR: The research progress and related mechanisms of the role of mRNA m6A methylation in the nervous system from the aspects of neural stem cells, learning and memory, brain development, axon growth and glioblastoma are reviewed.
Abstract: Epitranscriptomics, also known as “RNA epigenetics”, is a chemical modification for RNA regulation. Ribonucleic acid (RNA) methylation is considered to be a major discovery following the deoxyribonucleic acid (DNA) and histone methylation. Messenger RNA (mRNA) methylation modification accounts for more than 60% of all RNA modifications and N6-methyladenosine (m6A) is known as one of the most common type of eukaryotic mRNA methylation modifications in current. The m6A modification is a dynamic reversible modification, which can directly or indirectly affect biological processes, such as RNA degradation, translation and splicing, and can play important biological roles in vivo. This article introduces the mRNA m6A methylation modification enzymes and binding proteins, and reviews the research progress and related mechanisms of the role of mRNA m6A methylation in the nervous system from the aspects of neural stem cells, learning and memory, brain development, axon growth and glioblastoma.

69 citations

References
More filters
Journal ArticleDOI
TL;DR: It is concluded that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward.
Abstract: Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal. Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin. We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.

124 citations


"An obesity-associated risk allele w..." refers background in this paper

  • ...Moreover, experiments in rodents show that changes in FTO expression levels in the hypothalamus affect feeding behaviour (Frederiksen et al., 2007; Olszewski et al., 2009; Tung et al., 2010)....

    [...]

Journal ArticleDOI
TL;DR: Both self-report and behavioral measures indicate that high impulsivity is a risk factor for a range of maladaptive behaviors, including over- or binge eating.
Abstract: Impulsivity can be defined as a predisposition toward rapid, unplanned reactions to internal or external stimuli regardless of negative consequences of these reactions for the impulsive individual or for others (Moeller et al., 2001). It is a multifaceted construct and there is a range of methods available for its measurement. Two of the most often used methods are self-report instruments and behavioral tasks (e.g., go/no-go tasks and delay discounting tasks). Self-reported impulsivity is positively correlated with impulsive reactions in behavioral measures, yet correlations are often weak and inconsistent (Logan et al., 1997; Lijffijt et al., 2004; Enticott et al., 2006; Reynolds et al., 2006; Cyders and Coskunpinar, 2011). It is assumed that self-report questionnaires represent impulsivity as a stable trait while behavioral tasks are subject to state-dependent variations. Nonetheless, both self-report and behavioral measures indicate that high impulsivity is a risk factor for a range of maladaptive behaviors, including over- or binge eating (Guerrieri et al., 2008; Waxman, 2009).

108 citations


"An obesity-associated risk allele w..." refers result in this paper

  • ...Thus, the AA genotype in our cohort confirms previous reports equating impulsivity with obesity/overeating (Meule, 2013) specifically in one study which also found a negative correlation between BIS and BMI in males (Dietrich et al....

    [...]

  • ...…scales for the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS), which measure punishment and reward sensitivity, respectively, are two such tools which correlate with inactivity and poor diet (Carver & White, 1994; Voigt et al., 2009; Meule, 2013; Dietrich et al., 2014)....

    [...]

  • ...Thus, the AA genotype in our cohort confirms previous reports equating impulsivity with obesity/overeating (Meule, 2013) specifically in one study which also found a negative correlation between BIS and BMI in males (Dietrich et al., 2014)....

    [...]

  • ...Lastly, we corroborate our findings in the imaging study with personality measures from the BIS and BAS scales, as obesity is associated with anomalies in both (Carver & White, 1994; Voigt et al., 2009; Meule, 2013; Dietrich et al., 2014)....

    [...]

Journal ArticleDOI
TL;DR: Findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.
Abstract: Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and Positron emission tomography in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal, and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. These findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues. Hum Brain Mapp, 36:120–136, 2015. © 2014 Wiley Periodicals, Inc.

104 citations


"An obesity-associated risk allele w..." refers background in this paper

  • ...Moreover, experiments in rodents show that changes in FTO expression levels in the hypothalamus affect feeding behaviour (Frederiksen et al., 2007; Olszewski et al., 2009; Tung et al., 2010)....

    [...]

Journal ArticleDOI
TL;DR: Body weight status was not only associated with eating behavior (cognitive restraint and disinhibition), but also with personality factors not inherently related to an eating context (BIS/BAS).
Abstract: †Behavioral and personality characteristics are factors that may jointly regulate body weight. This study explored the relationship between body mass index (BMI) and selfreported behavioral and personality measures. These measures included eating behavior (based on the Three-Factor Eating Questionnaire; Stunkard and Messick, 1985), sensitivity to reward and punishment (based on the Behavioral Inhibition System/Behavioral Activation System (BIS/BAS) scales )( Carver and White, 1994) and self-reported impulsivity (based on the Barratt Impulsiveness Scale-11; Patton et al., 1995). We found an inverted U-shaped relationship between restrained eating and BMI. This relationship was moderated by the level of disinhibited eating. Independent of eating behavior, BIS and BAS responsiveness were associated with BMI in a gender-specific manner with negative relationships for men and positive relationships for women. Together, eating behavior and BIS/BAS responsiveness accounted for a substantial proportion of BMI variance (men: ∼25%, women: ∼32%). A direct relationship between self-reported impulsivity and BMI was not observed. In summary, our results demonstrate a system of linear and non-linear relationships between the investigated factors and BMI. Moreover, body weight status was not only associated with eating behavior (cognitive restraint and disinhibition), but also with personality factors not inherently related to an eating context (BIS/BAS). Importantly, these relationships differ between men and women.

96 citations


"An obesity-associated risk allele w..." refers result in this paper

  • ...…scales for the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS), which measure punishment and reward sensitivity, respectively, are two such tools which correlate with inactivity and poor diet (Carver & White, 1994; Voigt et al., 2009; Meule, 2013; Dietrich et al., 2014)....

    [...]

  • ...Thus, the AA genotype in our cohort confirms previous reports equating impulsivity with obesity/overeating (Meule, 2013) specifically in one study which also found a negative correlation between BIS and BMI in males (Dietrich et al., 2014)....

    [...]

  • ...Lastly, we corroborate our findings in the imaging study with personality measures from the BIS and BAS scales, as obesity is associated with anomalies in both (Carver & White, 1994; Voigt et al., 2009; Meule, 2013; Dietrich et al., 2014)....

    [...]

Journal ArticleDOI
TL;DR: It is demonstrated that gene variants of FTO affect dopamine-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans during a reward learning task, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity.
Abstract: 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.

75 citations

Related Papers (5)
Frequently Asked Questions (1)
Q1. What are the contributions in this paper?

56 To this end, the authors examined how an obesity risk-allele for the FTO gene affects brain activity in 57 response to food images of different caloric content via fMRI. Their results suggest that the two 66 genotypes are associated with differential neural processing of food images, which may 67 influence weight status through diminished impulse control and reward processing.