A Brain Imaging Approach for Identifying Hormonal Mechanisms Underlying Satiety

描述（由申请人提供）：我们每天多次看到食物或食物的代表，并评估食物对我们来说是否好看。如果确实如此，我们就会平衡外部因素，比如社会环境或一天中的时间，与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，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，从而影响某种食物在那一刻是否令人食欲。通过她的K23奖，舒尔博士已经证明，在基线上，被认为是“使人发胖”的食物的照片会激活与食欲和奖励处理有关的大脑区域，包括下丘脑、伏隔核和眶额叶皮层。这种活动可能会因食物摄入而减少，这表明它反映了与饱腹感有关的潜在大脑机制。我们现在建议研究这些大脑活动变化的机制，通过询问它们是否与胰高血糖素样肽-1 （GLP-1）的作用直接相关，GLP-1是一种饱腹感信号。GLP-1是由肠道细胞对营养物质的反应释放，抑制食物摄入，其作用可被GLP-1受体拮抗剂exendin-阻断[9-39]。在两项随机、对照、交叉研究中，我们将评估exendin-[9-39]输注是否能逆转glp -1介导的食物摄入和大脑对视觉食物线索的反应。我们的科学目标是：1)建立exendin-[9-39]阻断人类GLP-1介导的饱腹感作用的剂量-反应曲线；2)测试一顿饭是否需要内源性GLP-1信号传导来降低人类大脑对视觉食物线索的反应。我们假设exendin-[9-39]会降低一顿饭在抑制随后的食物摄入和减少视觉食物线索在奖励通路中的激活方面的作用。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，这一有前途的研究方向与我们这个时代一些最紧迫的公共健康问题直接相关：肥胖和营养过剩。我们希望从最基本的层面上研究影响我们饱腹感的机制，最终会产生新的行为或药物策略来预防和治疗肥胖。

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.