Hypothalamic fMRI response to nutrients

描述（由申请人提供）：动物研究已经确立了下丘脑在控制食欲和能量消耗中的重要性。大脑这个区域内的核整合来自脂肪组织的输入，反映身体脂肪的储存，以及胃肠道的输入，反映摄入食物的数量和类型。这些传入信号触发食物摄入和能量消耗的变化，其机制既包括神经元细胞电活动的即时改变，也包括激素受体结合介导的相对较慢的影响。虽然这些中央综合中心控制体重调节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尚不清楚。这在很大程度上是由于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。功能性核磁共振成像（fMRI）是一种非侵入性、非放射性的成像技术，可以检测到大脑中神经元电活动的实时变化，误差在几毫米以内。功能磁共振成像（fMRI）被用于研究大脑对摄入葡萄糖的反应，并显示出瘦人与肥胖者在这方面的反应存在差异。然而，关于这些营养素差异的特异性（与肠道激素相反）以及不同宏量营养素与参与人类体重调节的中心中心的相互作用的问题仍然存在。这项试点资助的提案将汇集具有临床研究背景的研究人员，肥胖的基本电生理和神经内分泌机制，以及fMRI成像，以更好地了解营养物质如何影响下丘脑和脑干区域的大脑活动，这些区域与人类体重调节有关。第一个目标是使用功能磁共振成像来确定瘦人和肥胖者的下丘脑和脑干对静脉注射葡萄糖和果糖的反应。第二个目标是确定在啮齿类动物模型中，脂质是否会影响高脂肪饮食中体重增加所提示的中枢葡萄糖反应性。从这些研究中获得的经验和数据将用于未来关于混合膳食对大脑活动的影响的建议，长期饲喂不同常量营养素含量的饮食，以及单独或组合的肠道源性激素和脂肪细胞激素（如瘦素）的输注。同时采集血液中营养物质、胰岛素、瘦素和其他与体重调节有关的激素水平，将有助于了解它们在大脑体重调节中心的功能磁共振成像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大脑是如何受到糖和脂肪的影响的。这些研究将帮助我们更好地理解为什么饮食的改变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.