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。在大脑的这个区域内的核团整合来自脂肪组织的输入，反映身体脂肪储存和胃肠道的输入，反映摄入的食物的量和类型。这些传入信号通过涉及神经元细胞电活动的立即改变和通过受体结合介导的相对较慢的效应的机制触发食物摄入和能量消耗的变化。虽然这些控制体重调节的中央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尚不清楚。这在很大程度上是由于缺乏可用于研究人类体内对各种效应物的神经元反应的工具。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，可以检测大脑中神经元电活动的实时变化，精确到几毫米以内。功能磁共振成像已被用于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的这种反应的差异。然而，关于营养素（与肠道激素相反）的这些差异的特异性以及不同常量营养素与人类体重调节中心的相互作用仍然存在问题。这项试点拨款的提案将汇集具有临床研究背景的研究人员，肥胖的基本电生理学和神经内分泌机制，以及fMRI成像，以更好地了解营养素如何影响下丘脑和脑干区域的大脑活动，这些区域涉及人类的体重调节。第一个目标将使用功能磁共振成像来确定下丘脑和脑干对静脉注射葡萄糖和果糖的反应，在瘦和肥胖的受试者。第二个目标将确定脂质是否影响中枢葡萄糖反应性，如啮齿动物模型中高脂饮食的体重增加所示。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、长期喂食不同大量营养素含量的饮食以及输注肠道来源的激素的单独和组合对大脑活动的影响的建议。响应膳食和瘦素等脂肪细胞激素而分泌。同时对血液进行采样，检测营养素、胰岛素、瘦素和其他参与体重调节的激素的水平，将有助于深入了解它们在大脑体重调节中心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MRI扫描来探索大脑如何受到糖和脂肪的影响。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轻。

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.