Gastrointestional Integration and Feeding

响应于营养物的存在而从胃肠道产生的信号对于胃肠道的功能是重要的。 控制食物摄入。在摄入过程中，多个胃肠道部位受到营养消化的刺激 这种刺激启动局部胃肠道活动，产生神经和肽 提供关于胃肠道内容物的性质和量的反馈信息的信号。的能力 已经很好地证明了单个肠肽影响食物摄入。目前的实验 建议采取转化方法来检查肠肽激动剂组合的能力 化合物对减肥有有益的效果。治疗肥胖症的一些药理学方法 目前已有治疗方法，但其疗效有限，且无法达到减肥手术的效果， 产生显着和持续减少多余的重量。拟议的实验将检查多个 肽激动剂组合在啮齿动物和非人灵长类动物模型中的作用。在目标1中，我们 确定CCK、GLP-1和胰淀素激动剂的配对剂量组合可具有相加性的程度 或对胃排空、食物摄入和体重的协同作用。我们将研究短期 使用瘦大鼠和恒河猴的相互作用以及长期剂量组合对体重的影响 使用DIO大鼠和我们新的Bonnet猕猴肥胖模型。其他实验将侧重于 维持DIO大鼠热量限制引起的体重减轻的剂量组合。在目标2中，我们将 开始研究潜在的机制，潜在的能力，肠道肽剂量组合，以减少食物 通过评估激动剂组合对适口性和奖励措施的影响， 检查短暂的舔取和进行性比率反应。在目标3中，我们将确定 剂量组合的相互作用及其对基因表达和神经元信号传导途径的影响。我们 将使用c-fos作为神经激活的标记来识别显示协同相互作用的大脑部位。我们 将检测肽、神经递质和受体mRNA表达的变化， 激动剂对食物摄入和体重的协同相互作用的潜在机制， 研究剂量组合如何调节信号通路的活性， 在肽激动剂的摄食抑制作用中的作用。这些实验将共同测试 假设肠肽激动剂化合物的组合可以提供一种重要的方法， 目前肥胖症流行。减肥手术是目前唯一成功的长期减肥策略， 严重肥胖。减肥手术导致肠道肽分泌和模仿的显著改变 这与长效肠肽激动剂的组合的方面可以提供侵入性较小的方法， 促进减肥。

Signals arising from the gastrointestinal tract in response to the presence of nutrients are important to the control of food intake. During ingestion, multiple gastrointestinal sites are stimulated by nutrient digestion products and this stimulation initiates local gastrointestinal actions and produces both neural and peptide signals that provide feedback information on the nature and amount of gastrointestinal contents. The ability of individual gut peptides to affect food intake has been well demonstrated. The experiments in the current proposal take a translational approach to examine the ability of combinations of gut peptide agonist compounds to have beneficial effects on weight loss. A number of pharmacological approaches for obesity treatment are currently available but their efficacy is limited and does not approach that of bariatric surgery to produce significant and sustained reduction in excess weight. The proposed experiments will examine multiple actions of peptide agonist combinations in both rodent and nonhuman primate models. In Aim 1, we will identify the degree to which paired dose combinations of CCK, GLP-1 and amylin agonists can have additive or synergistic effects on gastric emptying, food intake and body weight. We will examine short-term interactions using lean rats and rhesus monkeys and the effects of chronic dose combinations on body weight using DIO rats and our novel Bonnet macaque obesity model. Additional experiments will focus on the ability of dose combinations to maintain weight loss produced by caloric restriction in DIO rats. In Aim 2, we will begin to examine potential mechanisms underlying the ability of gut peptide dose combinations to reduce food intake and body by assessing the effects of agonist combinations on measures of palatability and reward by examining brief access licking and progressive ratio responding. In Aim 3, we will identify neural sites of interaction for dose combinations and their effects on gene expression and neuronal signaling pathways. We will use c-fos as a marker of neural activation to identify brain sites demonstrating synergistic interactions. We will examine changes in mRNA expression for peptides, neurotransmitters and receptors further investigate mechanisms underlying the synergistic interactions of the agonists on food intake and body weight by examining how dose combination modulate activity in signaling pathways that have been demonstrated to play roles in the feeding inhibitory actions of the peptide agonists. Together these experiments will test the overall hypothesis that combinations of gut peptide agonist compounds can provide an important approach in the current obesity epidemic. Bariatric surgery is the only current successful long-term weight loss strategy for severe obesity. Bariatric surgery results in significant alterations in gut peptide secretion and mimicking aspects of this with combinations of long acting gut peptide agonists may provide a less invasive approach to promote weight loss.