Autonomic Regulation of Food Intake and Metabolism

描述(由申请人提供)：需要平衡控制食物摄入量和能量消耗，以保持体重在正常范围内，并避免肥胖的发展，肥胖已达到流行程度，并与代价高昂的次级健康问题有关。尾侧脑干中的神经回路被认为在控制食物摄取和能量平衡方面发挥着关键作用，因为它们从消化道接收信息，并组织必要的口咽和自主神经反应的运动模式。这一提议的基本假设是，下丘脑中携带较长期代谢和认知信息的其他关键回路，调节主要与短期反射动作有关的脑干尾部回路，以实现整体内环境平衡调节。 我们和其他人的初步工作表明：(1)表达黑素细胞刺激素(a-MSH)和较少程度的刺鼠相关蛋白(AgRP)的“喂食肽”的神经元投射到尾侧脑干中接受肠道信号并高表达黑素皮质素MC4受体的神经元；(2)α-MSH和AgRP及其稳定的类似物直接应用于尾部脑干，调节摄食量和进食量，以及孤束核和迷走神经运动核神经元的电生理特性和细胞内信号传递。 现在我们建议研究α-MSH和AgRP调节摄食控制的基本脑干过程的神经生理学机制。在三个特定的目标中，我们将集中于(1)这两个肽对食物结构和饱腹感机制的影响，(2)下行的a-MSH和AgRP投射和背侧迷走神经复合体中的受体神经元的连接和神经化学，以及(3)内脏迷走神经和下丘脑信号整合导致饱足感和食物摄入量改变的神经生理和分子机制。我们的多维方法使用最先进的行为、解剖学以及体内和体外电生理和分子技术，将提供有关能量平衡调节的关键信息，并将有助于开发预防或对抗肥胖的治疗方法。

DESCRIPTION (provided by applicant): A balanced control of food intake and energy expenditure is required to keep body weight in the normal range and to avoid development of obesity, which has reached epidemic proportions and is associated with costly secondary health problems. Neural circuits in the caudal brainstem are thought to play a key role in the control of food intake and energy balance, as they receive information from the alimentary canal and organize the necessary motor patterns for oropharyngeal and autonomic responses. The basic assumption of this proposal is that other key circuits in the hypothalamus, carrying longer-term metabolic and cognitive information, modulate caudal brainstem circuits concerned primarily with short-term reflex action, to achieve overall homeostatic regulation. Preliminary work by us and others has shown that (1) hypothalamic neurons expressing the "feeding peptides" melanocyte-stimulating hormone (a-MSH) and to a lesser extent agouti-related protein (AgRP), project to neurons in the caudal brainstem that receive gut signals and highly express melanocortin MC4- receptors, and (2) alpha-MSH and AgRP and their stable analogs applied directly to the caudal brainstem modulate food intake and meal size, as well as electrophysiological properties and intracellular signaling in neurons of the solitary nucleus and vagal motor nucleus. Now we propose to investigate the neurophysiological mechanisms by which alpha-MSH and AgRP modulate basic brainstem processes of ingestive control. In three specific aims we will focus on (1) the effects of the two peptides on meal structure and satiety mechanisms, (2) the connectivity and neurochemistry of the descending a-MSH and AgRP projections and the recipient neurons in the dorsal vagal complex, and (3) the neurophysiological and molecular mechanisms underlying the integration of visceral vagal and hypothalamic signals leading to changes in satiation and food intake. Our multidimensional approach using state-of-the-art behavioral, anatomical, as well as in vivo and in vitro electrophysiological and molecular techniques will provide crucial information about regulation of energy balance and will help develop therapies to prevent or combat obesity.