Background: Variants in the first intron of the fat mass and obesityassociated (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. Objective: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. Design: 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 lowerrisk 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 functionalMRI scans acquired before and after a standardized meal. Results: Higher-risk participants reported less subjective fullness (χ 2 = 7.48, P < 0.01), rated calorie-dense food as more appealing (χ 2 = 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 (R 2 = 0.29, P = 0.04) and this relation was particularly strong in the dorsal striatum (R 2 = 0.28, P = 0.01), amygdala (R 2 = 0.28, P = 0.03), and ventral tegmental area/substantia nigra (R 2 = 0.27, P = 0.01). Conclusion: The findings are consistent with a model inwhich 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.
Bibliographical noteFunding Information:
Supported by funding provided by DK089036, DK098466, DK52431, and DK026687. Additional assistance was provided by the University of Washington’s Nutrition Obesity Research Center (P30 DK035816), Diabetes Research Center (P30 DK017047), and the Institute of Translational Health Sciences (UL1 TR000423).
- Appetite regulation
- Food cues