A twin study of obesity pathogenesis using fMRI

描述(由申请人提供)：双胞胎研究为体重调节的遗传性质提供了决定性的证据，表明体重增加趋势的个体差异可以通过基因和营养之间的相互作用来解释。将基因与体重增加联系起来的确切机制尚不清楚，但它们对于理解常见肥胖症的发病机制至关重要。我们的目标是确定在现代食物环境中导致体重增加的遗传易感性的中枢神经系统(CNS)机制。为此，我们将使用神经成像来评估潜在的中枢神经系统机制，并使用双研究方法来确定这些机制的遗传基础及其与肥胖易感性的联系。我们和其他人使用了功能磁共振成像(FMRI)来证明，食物的视觉图像有力地刺激了大脑中活跃的区域，这些区域负责调节能量平衡、奖励和行为的认知控制。这些神经反应是否有遗传基础尚不确定。先前的研究表明，肥胖者对可能促进暴饮暴食的食物暗示的大脑反应发生了变化。人类和动物的研究也表明，肥胖者的饱腹感受损。为了研究这些理论，我们将使用带有视觉食物提示的功能磁共振成像，并通过功能连通性分析在系统水平上检查大脑功能。因此，我们将提供新的数据，说明在肥胖人群中观察到的大脑对食物提示的反应的差异，以及饱腹感受损在多大程度上代表了遗传倾向与潜在的可改变的环境中介或获得性特征。我们将在从华盛顿大学双胞胎登记处招募的两个双胞胎样本中实施我们建立的功能磁共振成像方案，以测量大脑对视觉食物线索的反应。通过随机抽取20对单合子样本，我们可以测试遗传因素是否可以解释大脑反应的个体差异。我们还将收集21对与体重指数不一致的同卵双胞胎和21对同性异卵双胞胎的目标样本，以：1)确定身体脂肪质量是否与大脑对视觉食物线索的反应有关，并确定这种联系是由遗传因素还是后天因素介导的；2)确定饱腹感受损是否与身体脂肪质量有关，如果是，则确定饱腹感处理过程中的外周或中枢异常是否导致损害。所有双胞胎都将接受脂肪质量和肥胖相关(FTO)基因的变异等位基因的基因分型，FTO基因是最常见的肥胖易感基因之一，目的是比较有FTO基因变异和没有FTO基因变异的双胞胎对视觉食物提示的大脑反应。这项提议有可能推进大脑调节食欲和饱腹感的科学知识。它还将提供对中枢神经系统机制的见解，通过这些机制，遗传因素可能使个人易于肥胖，从而指导未来的研究并针对高风险人群进行干预。

DESCRIPTION (provided by applicant): Twin studies have provided decisive evidence for the hereditary nature of body weight regulation, demonstrating that individual differences in tendencies to gain weight can be explained by an interaction between genotype and nutrition. The exact mechanisms that connect genes to weight gain remain unknown, but they are crucial to understanding the pathogenesis of common obesity. Our goal is to identify central nervous system (CNS) mechanisms that contribute to genetic susceptibility to weight gain in the modern food environment. To this end, we will use neuroimaging to assess potential CNS mechanisms, and twin research methods to establish the mechanisms' genetic basis and their link to susceptibility to obesity. We, and others, have used functional magnetic resonance imaging (fMRI) to demonstrate that visual images of food powerfully stimulate brain areas active in regulating energy homeostasis, reward, and cognitive control of behavior. Whether these neural responses have a genetic basis is uncertain. Prior research suggests that obese persons have alterations in brain response to food cues that might promote overeating. Both human and animal studies also suggest that satiety is impaired in obese persons. To investigate these theories, we will use fMRI with visual food cues, augmented by functional connectivity analyses that examine brain function at a systems level. We will thereby provide new data on the extent to which observed differences in brain response to food cues among obese persons, as well as impaired satiety, represent genetic predispositions vs. potentially modifiable environmentally-mediated or acquired traits. We will implement our established fMRI protocol for measuring brain response to visual food cues in 2 twin samples recruited from the University of Washington Twin Registry. A random sample of 20 monozygotic pairs will allow us to test whether inherited factors can account for individual differences in brain response. We will also assemble a targeted sample of 21 monozygotic and 21 same-sex dizygotic twin pairs discordant for body mass index to: 1) determine whether body fat mass is associated with brain response to visual food cues and establish whether the association is mediated by inherited or acquired factors, and 2) determine whether impaired satiety is associated with body fat mass and, if so, whether impairments derive from peripheral or central abnormalities in satiety processing. All twins will be genotyped for variant alleles in the fat mass and obesity-associated (FTO) gene, one of the most common obesity susceptibility genes, in order to compare brain response to visual food cues in twins with and without FTO gene variants. This proposal has the potential to advance scientific knowledge of the brain's regulation of appetite and satiety. It will also provide insights into the CNS mechanisms by which inherited factors might predispose individuals to obesity, thereby guiding future research and targeting interventions for those at highest risk.