Gastrointestional Integration and Feeding

来自胃肠道的信号对营养物质的存在起着重要作用 控制食物摄入量。在摄取过程中，营养物质的消化会刺激多个胃肠道部位 产品，这种刺激启动局部胃肠道活动，并产生神经和肽 提供有关胃肠道内容物的性质和数量的反馈信息的信号。的能力 单独的肠肽影响食物摄入量已经得到了很好的证明。当前的实验 建议采用翻译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作用。治疗肥胖症的一些药理学方法 目前有可用的治疗方法，但其疗效有限，无法接近减肥手术的效果 显著并持续地减少超重。拟议的实验将检查多个 多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，我们将 确定CCK、GLP-1和胰淀素激动剂的配对剂量组合可以相加的程度 或对胃排空、食物摄入量和体重的协同效应。我们将考察短期 瘦身大鼠与恒河猴的相互作用及慢性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。更多的实验将集中在能力上 剂量组合以维持DIO大鼠因热量限制而产生的体重减轻。在目标2中，我们将 开始研究肠道多肽剂量组合减少食物摄入能力的潜在机制 摄入量和身体，通过评估激动剂组合对适口性和奖赏的影响 检查简短访问点击和递增比率响应。在目标3中，我们将确定 剂量组合的交互作用及其对基因表达和神经元信号通路的影响。我们 将使用c-fos作为神经激活的标志，以确定显示协同作用的大脑部位。我们 将检测多肽、神经递质和受体的mRNA表达的变化进一步研究 激动剂对摄食量和体重协同作用的机制 研究组合如何调节已被证明发挥作用的信号通路中的活动 在多肽激动剂的摄食抑制作用中的作用。这些实验加在一起将检验整体 假设肠肽激动剂化合物的组合可以提供一种重要的方法 当前的肥胖症流行。减肥手术是目前唯一成功的长期减肥策略 严重肥胖。减肥手术导致肠肽分泌和模仿的显著变化 这些方面与长效肠肽激动剂的组合可能提供一种侵入性较小的方法 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.