obesity-associated risk allele within the

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. We 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. We tested 30 male participants homozygous for either the risk (A)- or non- 282 risk (T) allele of the fat mass and obesity associated ( FTO ) SNP rs9939609 (13 in the AA 283 group and 17 in the TT group). Participants were shown images of low-calorie (LC) food, 284 high-calorie (HC) food, or control images while blood-oxygen-level dependent (BOLD) 285 signals were obtained via fMRI. We found the AA genotype had increased brain activity 286 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 288 and precuneus) and reward (putamen). Moreover, while both genotypes had a similar distribution of BMI, ranging between normal-weight to obese in each genotype, we found that BMI was associated with differential activity within each genotype – with comparatively more brain regions associated with BMI in the AA genotype than in the TT genotype. Thus, discrimination between HC and LC foods may be handled differently for each genotype depending on BMI. Next, we corroborate our findings in the imaging study with personality questionnaires examining behavioral characteristics related to impulsivity and reward- processing: namely the Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) scales. We found that the BIS as well as subscales of the BAS correlated with BMI oppositely in each genotype. Thus, obesity within each genotype may stem from different behavioral characteristics. Our results suggest that this polymorphism of the FTO gene affects the processing of visual food stimuli differently, possibly involving emotion, self- image, and reward processing.