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

肥胖和相关的代谢紊乱已经成为一个巨大的公共健康问题。这项建议研究了整合脂肪激素瘦素和肠源性饱腹感信号CCK和GLP-1的神经电路，以及这些信号之间的相互作用对控制食物摄入量和体重的生理相关性。现有数据支持这一假设，即肥胖激素瘦素减少食物摄入量的部分原因是通过增强对胃肠道信号的饱腹感反应，包括JCCK。我们最近确定了瘦素与GLP-1的相互作用，但我们的数据表明，瘦素-CCK和瘦素-GLP-1的相互作用是通过不同的神经元途径介导的。在这里，我们建议通过部位特异性微量注射和基因治疗，在正常大鼠和由于基因突变而缺乏瘦素受体的大鼠中，识别和比较瘦素检测足以增强对GLP-1和CCK的反应的脑区。 接下来，我们将研究瘦素是否减少了食物的摄入，并增强了对 胃肠道营养素部分通过调节大鼠对内源性释放的GLP-1或CCK的敏感性来实现。 最后，我们将确定对GLP-I或CCK的敏感性改变是否在饮食诱导肥胖的发病机制中发挥作用当大鼠保持高脂肪饮食时，这会产生瘦素抵抗，这些研究将有助于澄清身体脂肪储存的变化如何导致食物大小的代偿性调整，以及这一过程中的缺陷如何可能导致肥胖和代谢紊乱，从而有可能显著提高我们对摄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.