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

肥胖及相关代谢紊乱已成为一个巨大的公共卫生问题。本研究旨在研究整合肥胖激素瘦素和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）输入的神经回路，以及这些信号之间相互作用与控制食物摄入和体重的生理相关性。现有数据支持肥胖激素瘦素减少食物摄入的假设，部分是通过增强对胃肠道信号的饱腹反应，包括CCK。我们最近确定瘦素在类似的河流中与GLP-1相互作用，但我们的数据表明，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，我们建议在正常大鼠和由于基因突变而缺乏瘦素受体的大鼠中，使用位点特异性微注射和基因治疗，确定并比较瘦素检测足以增强对GLP-1和CCK反应的大脑区域。

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.