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.
Summary (4 min read)
- 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.
- 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.
- 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.
- 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) .
- 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.
- 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.
- 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.
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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)....
"An obesity-associated risk allele w..." refers methods in this paper
...Bilateral masks of such areas were produced using the Wake Forest University Pickatlas toolbox (Maldjian et al., 2003) within SPM. Small volume corrections were performed on clusters trending towards significance (surpassing an uncorrected P 0.001 threshold but failing FWE-correction) only for…...
...produced using the Wake Forest University Pickatlas toolbox (Maldjian et al., 2003) within SPM....
"An obesity-associated risk allele w..." refers background in this paper
...of blood oxygen level-dependent (BOLD) responses to food images, we test whether the genotype homozygous for the at-risk allele for rs9939609 (which is A) (Dina et al., 2007; Frayling et al., 2007; Scuteri et al., 2007) affects brain activity differently from the homozygous genotype with the non-risk allele (T)....
...…level-dependent (BOLD) responses to food images, we test whether the genotype homozygous for the at-risk allele for rs9939609 (which is A) (Dina et al., 2007; Frayling et al., 2007; Scuteri et al., 2007) affects brain activity differently from the homozygous genotype with the non-risk allele (T)....
"An obesity-associated risk allele w..." refers background in this paper
...The PCC is a wellconnected and multifunctional brain area associated with emotional processing, and is a central node in the default mode network, involved in arousal/awareness, balancing external and internal thought, and emotion (Leech & Sharp, 2014)....
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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.