An fMRI Test of the Dynamic Vulnerability Model of Obesity: Risk Factor Plasticit

描述(由申请人提供)：与瘦人相比，肥胖的人对美味的食物图像/线索表现出更大的味觉/口腔体感和奖赏区域的响应，这预测了未来的体重增加(Yokum等人，在新闻中；Prelim研究；Stices等人，2008a，d，2010b；Stoeckel等人，2008)，符合肥胖的奖赏过量和诱因敏化模型(Berbridge， 2009年；Davis等人，2004年)。然而，肥胖与瘦人相比，纹状体奖赏区域中的多巴胺(DA)受体较少，表现出对美味食物摄入的纹状体反应减少，纹状体反应低预示着DA信号减少的遗传风险人群未来的体重增加(Felsted等人，2010；Stices等人，2008a，d；Wang等人，2001；Volkow等人，2008)，这与肥胖症的奖赏不足模型(Wang等人，2002b)一致。对这种混合发现的一种解释是，这些发现中的一些反映了最初的风险因素，另一些则是过量饮食的结果。解雇助理总检察长 奖赏区域的神经元在条件反射后从食物摄入量转变为预测食物摄入量的线索(Kiyatkin等人，1994；Schultz等人，1993)，过量进食导致大鼠D2受体密度、D2敏感性和奖赏敏感性降低(alsio等人，2010；Kelley等人)。以及人类对食物的纹状体反应(Stices等人，2010a)，这意味着过量进食会增加奖励区域的激励敏感化和下调调节。此外，对食物图像/线索的抑制区域反应减少预示着未来的暴饮暴食和体重增加(Cornier等人，2010年；普雷姆研究)。数据表明，肥胖风险青年最初表现出编码食物线索奖励价值的区域的更大响应性，加上编码食物糖和脂肪含量的味觉/口腔体感区域的更大响应性，以及抑制区域响应性的降低，这会导致过量饮食/体重增加，从而产生钝化的纹状体DA信号，奖励评估区域对食物提示的响应性增加，以及对食物刺激的抑制激活减少，从而增加进一步过量进食/体重增加的风险。我们建议使用一种新的重复测量功能磁共振设计来对这种动态脆弱性模型进行严格的测试，在这种设计中，青少年在4年内每年完成扫描。目的1：测试130名瘦削青少年的味觉/口腔躯体感觉和奖赏区域反应性升高，抑制区反应性降低，对不同糖/脂肪含量的可口食物图像、线索和食物摄入量，以及行为抑制控制缺陷/即刻奖赏偏差是否可以预测体脂百分比的初始增加。目的2：使用生长曲线模型来检验最初体脂和能量密度食物摄入量的增加是否预示着纹状体对美味食物接收的反应减少，对美味食物图像/线索的奖赏回路反应增加，对食物图像/线索的抑制区域反应减少，以及行为抑制控制缺陷/即时奖赏偏向增加。目的3：检验纹状体对美味食物的反应减少、对食物图像/线索的奖赏区域反应增加、对食物图像/线索的抑制区域反应减少、行为抑制控制缺陷/即刻奖赏偏差是否预测体脂百分比的进一步上升。

DESCRIPTION (provided by applicant): Obese vs lean humans show greater gustatory/oral somatosensory and reward region responsivity to palatable food images/cues and this predicts future weight gain (Yokum et al., in press; Prelim Studies; Stice et al., 2008a,d, 2010b; Stoeckel et al., 2008), in line with reward surfeit and incentive sensitization models of obesity (Berridge, 2009; Davis et al., 2004). Yet, obese vs lean humans have fewer dopamine (DA) receptors in striatal reward regions, show reduced striatal response to palatable food intake, and low striatal response predicts future weight gain in those at genetic risk for reduced DA signaling (Felsted et al., 2010; Stice et al., 2008a,d; Wang et al., 2001; Volkow et al., 2008), in line with the reward deficit model of obesity (Wang et al., 2002b). One explanation for the mixed findings is that some of these findings reflect initial risk factors and others result from overeating. Firing of DA neurons in reward regions shifts from food intake to cues that predict food intake after conditioning (Kiyatkin et al., 1994; Schultz et al., 1993) and overeating leads to reduced D2 receptor density, D2 sensitivity, and reward sensitivity in rats (Alsio et al., 2010; Kelley et al. 2003; Johnson & Kenny, 2010) and striatal response to food in humans (Stice et al., 2010a), implying that overeating leads to increased incentive sensitization and down-regulation of reward regions. Further, reduced inhibitory region response to food images/cues predicts future overeating and weight gain (Cornier et al., 2010; Prelim Studies). Data imply that youth at risk for obesity initially show greater responsivity of regions that encode the reward value of food cues, coupled with greater responsivity of gustatory/oral somatosensory regions that encode the sugar and fat content of foods, and with reduced inhibitory region responsivity, which lead to overeating/weight gain that produces blunted striatal DA signaling, increased responsivity of reward valuation regions to food cues, and reduced inhibitory activation in response to food stimuli, increasing risk for further overeating/weight gain. We propose to conduct a rigorous test of this dynamic-vulnerability model using a novel repeated measures fMRI design in which teens complete scans annually over 4 years. Aim 1: test whether elevated gustatory/oral somatosensory and reward region responsivity and reduced inhibitory region responsivity to palatable food images, cues, and intake of food varying in sugar/fat content, and behavioral inhibitory control deficits/immediate reward bias predict initial increases in % body fat in 130 lean teens. Aim 2: use growth curve models to test whether initial increases in % body fat and energy dense food intake predict future decreases in striatal response to palatable food receipt, increases in reward circuitry response to palatable food images/ cues, decreased inhibitory region response to food images/cues, and increased behavioral inhibitory control deficits/immediate reward bias. Aim 3: test whether decreased striatal response to palatable food, increased reward region response to food images/cues, reduced inhibitory region response to food images/cues, behavioral inhibitory control deficits/immediate reward bias predict further escalation in % body fat.