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

描述(由申请人提供)： 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。现有数据支持这样的假设，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(包括CCK)的饱腹感反应。我们最近已经确定瘦素与GLP-1的相互作用方式相似，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，使用部位特异性微量注射和基因治疗来识别和比较瘦素检测足以增强对GLP-1和CCK的反应的大脑区域。接下来，我们将研究瘦素是否通过调节大鼠对内源性释放的GLP-1或CCK的敏感性来减少食物摄入并增强对胃肠道营养物质的饱腹感反应。最后，我们将确定对GLP-1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，当大鼠保持高脂饮食时，高脂饮食会产生瘦素抵抗。总之，这些研究将有助于阐明体内脂肪储备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。这项研究的重点是大脑如何检测脂肪中储存的能量以及肠道中是否存在营养物质，然后将这些信息整合起来，以确定应该吃多少食物。具体地说，我们将研究调节这些影响的大脑区域，以及这些相互作用与正常摄食控制和肥胖发展的相关性。我们的研究将提高我们对调节食物摄入量和体重的神经回路的理解，并将有助于识别导致肥胖发生和维持的生物因素。

DESCRIPTION (provided by applicant): 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 peptide-1 (GLP-1), and the physiological relevance of the 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, including CCK. We have recently determined that leptin interacts in a similar manner 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-specific 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-1 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 of the neural control of feeding and body weight. Lay Description: This research focuses on how the brain detects stored energy in fat along with the presence of nutrients in the gut, and then integrates that information to determine how much food to eat. Specifically, we will examine the brain areas that mediate these effects, as well as the relevance of these interactions to normal control of feeding and the development of obesity. Our studies will improve our understanding of the neural circuitry that regulates food intake and body weight, and will help identify biological factors that contribute to the development and maintenance of obesity.