Departments of Medicine and Radiology, University of Washington, Seattle, WA.
Departments of Radiology, University of Washington, Seattle, WA.
Am J Clin Nutr. 2018 Feb 1;107(2):145-154. doi: 10.1093/ajcn/nqx029.
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.
脂肪量和肥胖相关（FTO）基因第一内含子的变异增加肥胖风险。具有“高风险”FTO 基因型的人表现出对高脂肪食物的偏好、饱腹感反应降低和更多的食物摄入，这与饱腹感受损一致。
我们试图寻找基于 FTO 基因型肥胖风险较高的人群中可能导致饱腹感受损的中枢神经系统机制。
我们在一个富含肥胖的样本中进行了一项横断面研究，该样本包括 20 名 FTO 基因 rs9939609 位点 AA（风险）基因型的高风险参与者和 94 名 AT 或 TT 基因型的低风险参与者。我们比较了主观食欲、食欲调节激素、自助餐的热量摄入以及在标准化餐后使用功能磁共振成像扫描在扩展饱腹感网络中对视觉食物线索的大脑反应。
高风险参与者报告的饱腹感较少（χ2 = 7.48，P < 0.01），认为高热量食物更有吸引力（χ2 = 3.92，P < 0.05），并且比低风险参与者多摄入约 350 卡路里（β = 348 卡路里，P = 0.03），即使在调整了脂肪或瘦体重后也是如此。餐前，高风险组在眶额内侧皮质中对“发胖”食物图像（与物体相比）的激活更大（β = 11.6；95%CI：1.5，21.7；P < 0.05）。餐后，高风险组在腹侧被盖区/黑质（β = 12.8；95%CI：2.7，23.0；P < 0.05）、杏仁核（β = 10.6；95%CI：0.7，20.5；P < 0.05）和腹侧纹状体（β = 6.9；95%CI：0.2，13.7；P < 0.05）中对“发胖”食物线索的激活更大。此外，在预先选择的扩展饱腹感网络中，餐后对“发胖”食物线索的激活与自助餐的能量摄入呈正相关（R2 = 0.29，P = 0.04），并且这种关系在背侧纹状体（R2 = 0.28，P = 0.01）、杏仁核（R2 = 0.28，P = 0.03）和腹侧被盖区/黑质（R2 = 0.27，P = 0.01）中尤其强烈。
这些发现与 FTO 等位基因变异通过中枢神经系统饱腹感处理受损增加肥胖风险的模型一致，从而增加食物摄入。本研究在 clinicaltrials.gov 注册为 NCT02483663。
