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证据，表明体重增加倾向的个体差异可以通过基因型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仍然未知，但它们对于理解常见肥胖的发病机制至关重要。我们的目标是确定中枢神经系统（CNS）的机制，有助于遗传易感性的体重增加，在现代食品环境。为此，我们将使用神经影像学来评估潜在的中枢神经系统机制，并使用双胞胎研究方法来建立机制的遗传基础及其与肥胖易感性的联系。 我们和其他人已经使用功能性磁共振成像（fMRI）来证明，食物的视觉图像强烈地刺激了活跃于调节能量稳态、奖励和行为认知控制的大脑区域。这些神经反应是否有遗传基础尚不确定。先前的研究表明，肥胖者的大脑对食物的反应可能会改变，这可能会促进暴饮暴食。人类和动物研究也表明，肥胖者的饱腹感受损。为了研究这些理论，我们将使用fMRI与视觉食物线索，增强功能连接分析，检查大脑功能在系统水平。因此，我们将提供新的数据，在何种程度上观察到的差异，大脑对肥胖人群中的食物线索的反应，以及饱腹感受损，代表遗传易感性与潜在的可修改的环境介导的或获得的性状。 我们将在从华盛顿大学双胞胎登记处招募的2名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。随机抽取20对同卵双胞胎样本，我们就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）确定体脂肪量是否与大脑对视觉食物线索的反应相关，并确定该相关性是否由遗传或后天因素介导，以及2）确定饱食感受损是否与体脂肪量相关，如果是，是否损伤源于饱腹感处理中的外周或中枢异常。所有双胞胎都将进行脂肪量和肥胖相关（FTO）基因（最常见的肥胖易感基因之一）中变异等位基因的基因分型，以比较有和没有FTO基因变异的双胞胎对视觉食物线索的大脑反应。 这一提议有可能推进大脑对食欲和饱腹感的调节的科学知识。它还将提供对遗传因素可能使个体易患肥胖症的CNS机制的见解，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.