An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning
An Obesity-Predisposing Variant of the FTO Gene Regulates D2R-Dependent Reward Learning
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DOI：
10.1523/jneurosci.1589-15.2015
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发表时间：
2015-09-09
影响因子：
5.3
通讯作者：
Tittgemeyer, Marc
中科院分区：
文献类型：
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作者：
Sevgi, Meltem;Rigoux, Lionel;Tittgemeyer, Marc
脂肪量和肥胖相关（FTO）基因的变异与肥胖有关。然而，这些遗传变异影响肥胖、行为和大脑的潜在神经生物学机制尚不清楚。鉴于Fto调节小鼠的D2/3R信号传导，我们在人类中测试了FTO的变体是否会与ANKK 1基因的变体相互作用，ANKK 1基因改变了D2 R信号传导，也与肥胖有关。在行为和fMRI研究中，我们证明了FTO的基因变体影响多巴胺（D2）依赖性中脑对奖励学习的反应以及与人类从负面结果中学习相关的行为反应。此外，动态因果模型证实，FTO变体调节中纹状体-前额叶区域的基本奖励回路中的连接性，这表明遗传易感性不仅在肥胖症中改变奖励处理，而且在其他具有改变的D2 R依赖性冲动控制的疾病中也改变了奖励处理，例如成瘾。
Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction.