A Brain Imaging Approach for Identifying Hormonal Mechanisms Underlying Satiety

描述（由申请人提供）：每天有很多次，我们看到食物或食物的代表，并评估食物是否对我们来说好看。如果是这样，我们就会平衡外部因素，如社会状况或一天中的时间，以及关于我们饥饿状态的内部信号，以决定吃什么和什么时候吃。然而，最近的功能性磁共振成像（fMRI）研究表明，内部信号，如调节食欲和饱腹感的激素，部分通过作用于神经回路来影响给定食物在那一刻是否显得有食欲，从而控制我们的食物摄入。通过她的K23奖，Schur博士已经证明，在基线上，被认为是“增肥”的食物的照片激活了与食欲和奖励处理有关的大脑区域，包括下丘脑，丘脑核和眶额皮质。这种活动被食物摄入有力地减少，这表明它反映了与饱腹感有关的潜在大脑机制。我们现在建议通过询问它们是否与胰高血糖素样肽-1（GLP-1）（一种饱腹感信号）的作用直接相关来研究大脑活动中这些变化的机制。GLP-1由肠道细胞响应营养物质释放，抑制食物摄入，其作用可被GLP-1受体拮抗剂exendin-[9-39]阻断。在2项随机、对照、交叉研究中，我们将评估exendin-[9-39]输注是否逆转GLP-1介导的对食物摄入和大脑对视觉食物提示反应的影响。我们的科学目的是：1）建立exendin-[9-39]阻断GLP-1介导的人体饱腹感的剂量反应曲线，2）测试内源性GLP-1信号传导是否是膳食降低大脑对人类视觉食物线索反应的作用所必需的。我们假设exendin-[9-39]将减少一顿饭在抑制随后的食物摄入和减少奖励途径中对视觉食物线索的激活方面的作用。确定饱腹感在多大程度上是由食物奖励价值的降低引起的，这对理解人类的进食行为至关重要。此外，这一有前途的研究领域与我们这个时代最紧迫的公共卫生问题直接相关：肥胖和营养过剩。我们希望在最基本的层面上调查影响我们饱腹感的机制，最终将导致肥胖预防和治疗的新行为或药理学策略。 公共卫生相关性：肥胖和肥胖的健康并发症是我们这个时代最重要的公共卫生问题之一。这项研究可能为行为或药物治疗提供途径，以帮助实现和维持减肥。

DESCRIPTION (provided by applicant): Many times each day, we see food or representations of food and evaluate whether or not the food looks good to us. If it does, we then balance external factors, such as the social situation or time of day, against internal signals about our hunger state in order to decide what and when to eat. However, recent functional magnetic resonance imaging (fMRI) studies suggest that internal signals, such as hormones regulating appetite and satiety, govern our food intake in part by acting on neural circuits to affect whether a given food appears appetizing at that moment. Through her K23 award, Dr. Schur has demonstrated that, at baseline, photographs of food perceived to be "fattening" activate brain regions involved in appetite and reward processing, including the hypothalamus, nucleus accumbens, and orbital frontal cortex. This activity is potently reduced by food intake, suggesting that it reflects underlying brain mechanisms involved in satiety. We now propose to study the mechanism of these changes in brain activity by asking if they are directly related to the action of glucagon-like peptide-1 (GLP-1), a satiety signal. GLP-1 is released by cells in the gut in response to nutrients, suppressing food intake, and its actions can be blocked by a GLP-1 receptor antagonist, exendin-[9-39]. In 2 randomized, controlled, crossover studies, we will assess whether exendin-[9-39] infusions reverse GLP-1-mediated effects on food intake and on brain response to visual food cues. Our scientific aims are 1) To establish a dose-response curve for the effect of exendin-[9-39] to block GLP-1-mediated satiety in humans, and 2) to test whether endogenous GLP-1 signaling is required for the effect of a meal to reduce brain response to visual food cues in humans. We hypothesize that exendin-[9-39] will diminish the effect of a meal in suppressing subsequent food intake and in reducing activation to visual food cues in reward pathways. Determining the extent to which the experience of satiety arises from a decrease in the reward value of food is fundamentally important to understanding human feeding behavior. In addition, this promising line of research is directly relevant to some of the most pressing public health issues of our time: obesity and overnutrition. We hope that investigating mechanisms affecting our perception of satiety at the most basic level will eventually result in novel behavioral or pharmacologic strategies for obesity prevention and treatment. PUBLIC HEALTH RELEVANCE: Obesity and the health complications of obesity are one of the most important public health concerns of our times. This research may suggest avenues for behavioral or pharmacologic treatment to aid in achieving and maintaining weight loss.