Melhorn SJ, Askren MK, Chung WK, Kratz M, Bosch TA, Tyagi V, Webb MF, De Leon MRB, Grabowski TJ, Leibel RL, Schur EA.
Variants in the first intron of the fat mass and obesity-associated (FTO) gene increase obesity risk. People with “high-risk” FTO genotypes exhibit preference for high-fat foods, reduced satiety responsiveness, and greater food intake consistent with impaired satiety.
We sought central nervous system mechanisms that might underlie impaired satiety perception in people with a higher risk of obesity based on their FTO genotype.
We performed a cross-sectional study in a sample that was enriched for obesity and included 20 higher-risk participants with the AA (risk) genotype at the rs9939609 locus of FTO and 94 lower-risk participants with either the AT or TT genotype. We compared subjective appetite, appetite-regulating hormones, caloric intake at a buffet meal, and brain response to visual food cues in an extended satiety network using functional MRI scans acquired before and after a standardized meal.
Higher-risk participants reported less subjective fullness (χ2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ2 = 3.92, P < 0.05), and consumed ∼350 more kilocalories than lower-risk participants (β = 348 kcal, P = 0.03), even after adjusting for fat or lean mass. Premeal, the higher-risk group had greater activation by “fattening” food images (compared with objects) in the medial orbital frontal cortex (β = 11.6; 95% CI: 1.5, 21.7; P < 0.05). Postmeal, the higher-risk subjects had greater activation by fattening (compared with nonfattening) food cues in the ventral tegmental area/substantia nigra (β = 12.8; 95% CI: 2.7, 23.0; P < 0.05), amygdala (β = 10.6; 95% CI: 0.7, 20.5; P < 0.05), and ventral striatum (β = 6.9; 95% CI: 0.2, 13.7; P < 0.05). Moreover, postmeal activation by fattening food cues within the preselected extended satiety network was positively associated with energy intake at the buffet meal (R2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R2 = 0.28, P = 0.01), amygdala (R2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R2 = 0.27, P = 0.01).
The findings are consistent with a model in which allelic variants in FTO raise obesity risk through impaired central nervous system satiety processing, thereby increasing food intake. This study is registered at clinicaltrials.gov as NCT02483663.
FTO genotype impacts food intake and corticolimbic activation. Am J Clin Nutr. 2018 Feb 1;107(2):145-154. doi: 10.1093/ajcn/nqx029.