Hypothalamic fMRI response to nutrients

描述(由申请人提供)：动物研究已经确定了下丘脑在控制食欲和能量消耗方面的重要性。大脑这一区域内的核团整合了来自脂肪组织和胃肠道的信息，脂肪组织反映了身体脂肪储存，胃肠道反映了摄入的食物的数量和类型。这些传入信号通过两种机制触发食物摄入量和能量消耗的变化，包括神经细胞电活动的即时变化和由激素受体结合介导的相对较慢的效应。虽然这些控制体重调节的中枢综合中心的概念在动物模型中得到了很好的研究，但这些发现对人类的重要性还不是很清楚。这在很大程度上是因为缺乏可用的工具来研究人类体内对各种效应器的神经元反应。功能核磁共振成像(FMRI)是一种非侵入性、非放射性的成像技术，它可以实时检测大脑中几毫米以内的神经元电活动的变化。功能磁共振成像已经被用来研究大脑对摄入葡萄糖的反应，并显示出瘦和肥胖受试者之间这种反应的差异。然而，关于营养素(而不是肠道激素)的这些差异的特殊性，以及不同的常量营养素与参与人体体重调节的中枢之间的相互作用，仍然存在疑问。这项试点拨款中的建议将把具有临床研究背景、肥胖的基本电生理和神经内分泌机制以及功能磁共振成像的研究人员聚集在一起，以更好地了解营养物质如何影响与人类体重调节有关的下丘脑和脑干区域的大脑活动。第一个目标将使用功能磁共振成像来确定精瘦和肥胖受试者下丘脑和脑干对静脉注射葡萄糖和果糖的反应。第二个目标将确定脂质是否会影响中枢葡萄糖反应，正如啮齿动物模型中高脂饮食的体重增加所表明的那样。从这些研究中获得的经验和数据将被用于未来对大脑活动的影响的建议中，这些建议包括混合膳食、长期喂养不同常量营养素含量的饮食，以及注射因膳食和瘦素等脂肪细胞激素而分泌的个别和组合的肠道衍生激素。同时采集血液中营养素、胰岛素、瘦素和其他参与体重调节的激素水平，将有助于了解它们在大脑体重调节中心功能磁共振信号变化中可能发挥的作用。这项研究将使用功能性核磁共振扫描来探索糖和脂肪是如何影响大脑的。这些研究将帮助我们更好地理解为什么饮食的变化可能会导致体重增加或减少。

DESCRIPTION (provided by applicant): Animal studies have established the importance of the hypothalamus in the control of appetite and energy expenditure. Nuclei within this area of the brain integrate inputs from adipose tissue reflecting body fat stores and the gastrointestinal tract reflecting the amount and types of food ingested. These afferent signals trigger changes in food intake and energy expenditure through mechanisms involving both immediate alterations in neuronal cell electrical activity and relatively slower effects mediated via hormone-receptor binding. While these concepts of a central integrative center controlling weight regulation are well studied in animal models, the importance of these findings to humans is less clear. This is in large part due to a lack of tools available to study neuronal responses to various effectors in-vivo in humans. Functional nuclear magnetic imaging (fMRI) is a non-invasive, non-radioactive imaging technique that detects real-time changes in neuronal electrical activity to within a few millimeters in the brain. fMRI has been used to study the brain's response to ingestion of glucose and shown differences in this response between lean and obese subjects. However, questions remain regarding the specificity of these differences for nutrients (as opposed to gut hormones) and interactions of different macronutrients with central centers involved in weight regulation in humans. The proposals in this pilot grant will bring together investigators with backgrounds in clinical research, basic electrophysiological and neuroendocrine mechanisms of obesity, and fMRI imaging to better understand how nutrients affect brain activity in hypothalamic and brainstem regions involved with weight regulation in humans. The first aim will use fMRI to determine hypothalamic and brainstem responses to intravenous glucose and fructose in lean and obese subjects. The second aim will determine if lipids affect central glucose responsiveness as suggested by weight gain on high-fat diets in rodent models. Experience and data gained from these studies will be used in future proposals of effects on brain activity to mixed meals, long-term feeding of diets of differing macronutrient content, as well as to infusions of individual and combinations of gut-derived hormones secreted in response to meals and adipocyte hormones such as leptin. Simultaneous sampling of blood for levels of nutrients, insulin, leptin, and other hormones involved in weight regulation will give insight into the role they may play in changes in fMRI signaling in weight regulation centers in the brain. Lay Description: This study will use functional MRI scanning to explore how the brain is affected by sugar and fat. These studies will help us to better understand why changes in the diet might lead to weight gain or loss.