A Brain Imaging Approach for Identifying Hormonal Mechanisms Underlying Satiety

描述(由申请者提供)：我们每天多次看到食物或食物的表示，并评估食物对我们来说是否好看。如果是这样的话，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，最近的功能磁共振成像(FMRI)研究表明，调节食欲和饱腹感的荷尔蒙等内部信号在一定程度上通过作用于神经回路来控制我们的食物摄入量，从而影响特定食物在那个时刻是否看起来有胃口。通过她的K23奖项，舒尔博士已经证明，在基线情况下，被认为会使人发胖的食物的照片激活了参与食欲和奖励处理的大脑区域，包括下丘脑、伏隔核和眼眶额叶皮质。这种活动被食物摄入量有效地减少了，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这些变化是否与饱腹感信号--胰高血糖素样肽-1(GLP-1)的作用直接相关来研究这些大脑活动变化的机制。GLP-1是肠道细胞对营养物质的反应，抑制食物摄取，其作用可被GLP-1受体拮抗剂exendin-[9-39]阻断。在两项随机对照交叉研究中，我们将评估输注Exendin-[9-39]是否逆转了GLP-1对食物摄入量和大脑对视觉食物提示的反应的影响。我们的科学目标是1)建立exendin-[9-39]阻断人类GLP-1介导的饱腹感的剂量-反应曲线，以及2)测试内源性GLP-1信号是否为一顿饭的效果所必需，以减少人类对视觉食物提示的大脑反应。我们假设Exendin-[9-39]会减弱一顿饭在抑制随后的食物摄取和减少对奖赏通路中视觉食物线索的激活方面的效果。确定食物奖赏价值的下降在多大程度上产生了饱腹感，对于理解人类的进食行为是至关重要的。此外，这一前景看好的研究与我们这个时代一些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，在最基本的水平上研究影响我们饱腹感的机制，最终将导致预防和治疗肥胖症的新的行为或药物策略。 公共卫生相关性：肥胖及其引发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。这项研究可能会提出行为或药物治疗的途径，以帮助实现和保持减肥。

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.