Brain integration of adiposity and satiety signals in the control of food intake

肥胖及其相关的代谢紊乱已成为一个巨大的公共卫生问题。本研究旨在探讨整合肥胖激素瘦素、肠源性饱腹感信号胆囊收缩素（CCK）和胰高血糖素样肽-1（GLP-1）的神经回路，以及这些信号之间相互作用对控制摄食量和体重的生理相关性。现有的数据支持这一假设，即肥胖激素瘦素通过增强对胃肠道信号（包括CCK）的饱腹感反应，部分地减少食物摄入。我们最近已经确定瘦素与GLP-1在sirnilar rrianrier中相互作用，但是我们的数据表明瘦素-CCK和瘦素-GLP-1相互作用是通过不同的神经通路介导的。在这里，我们提出鉴定和比较瘦素检测足以增强对GLP-1和CCK的反应的脑区域，在正常大鼠和由于基因突变而缺乏瘦素受体的大鼠中使用位点特异性显微注射和基因治疗。 接下来，我们将研究瘦素是否会减少食物摄入量并增强饱腹感反应， 部分通过调节大鼠对内源性释放的GLP-1或CCK的敏感性来调节胃肠道营养素。 最后，我们将确定当大鼠维持高脂饮食时，对GLP-1或CCK的敏感性改变是否在饮食诱导的肥胖症的发病机制中起作用，这产生了瘦素抵抗，这些研究将有助于阐明体内脂肪储存的变化如何导致膳食量的代偿性调整，以及在这一过程中的缺陷如何导致肥胖和代谢紊乱，因此有可能大大提高我们对进食和体重的神经控制的理解。

Obesity and related metabolic disorders have become a tremendous public health problem. This proposal Investigates the neural circuitry that Integrates input from the adiposity hormone leptin and the gut-derived satiety signals cholecystokinin (CCK) and glucagon-like peptlde-1 (GLP-1), and the physiological relevance ofthe interactions between these signals for the control of food Intake and body weight. Available data support the hypothesis that the adiposity hormone leptin reduces food Intake in part by enhancing satiety responses to gastrointestinal signals, Includingj CCK. We have recently determined that leptin Interacts In a sirnilar rrianrier with GLP-1, but our data suggest that the leptin-CCK and leptin-GLP-1 interactions are mediated through different neuronal pathways, Here, we propose to Identify and compare brain areas In which leptin detection Is sufficient to enhance the responses to GLP-1 and CCK, using site-speclfic microinjections and gene therapy In normal rats and rats that lack leptin receptors due to genetic mutation. Next, we will Investigate whether leptin reduces food Intake and enhances the satiety response to gastrointestinal nutrients in part by modulating rats' sensitivity to endogenously released GLP-1 or CCK. Finally, we will determine whether altered sensitivity to GLP-i or CCK plays a role in the pathogenesis of diet-Induced obesity when rats are maintained on a high-fat diet, which produces leptin resistance, together, these studies will help to clarify how changes In body fat stores lead to compensatory adjustments in meal size, as well as how defects In this process may lead to obesity and metabolic disorders, and thus have the potential to significantly advance our understanding ofthe neural control of feeding and body weight.