Discovery and characterization of a novel natural product for the treatment of both diabetes and obesity

项目摘要 尽管2型糖尿病（T2 D）治疗的常用药物广泛应用，但 T2 D在美国继续上升。胰岛素抵抗和功能性β细胞群的进行性下降是两个关键 T2 D的驱动力。肥胖是发展T2 D的主要致病因素，这是一个重大障碍 用于许多T2 D患者的有效血糖控制。因此，鉴定可以同时 改善肥胖和促进胰岛素敏感性和β细胞功能将是更有效的策略， 预防和治疗T2 D。在寻找具有抗肥胖和抗高血糖活性的药物时，我们 首次发现橄榄叶提取物水解产生的小分子榄烯酸（EA） 橄榄苦苷就是这样一种非常有前途的化合物。令人兴奋的是，口服EA逆转了高血糖 同时也促进肥胖糖尿病小鼠的体重减轻和抑制食物摄入，值得注意的是，EA比其他药物更有效。 在控制高血糖症和肥胖症方面比二甲双胍更有效。有趣的是，EA诱导肽YY (PYY)和胰高血糖素样肽-1（GLP-1）从肠L-细胞分泌。在这项资助中，我们建议测试 假设EA是通过触发PYY同时治疗肥胖和糖尿病双重作用剂 和GLP-1分泌。目的1研究电针的抗糖尿病和减肥作用。在这方面，饮食- 诱导的肥胖小鼠和肥胖糖尿病db/db小鼠将通过口服管饲法每天接受一次EA治疗。的 将检查EA对肥胖糖尿病小鼠代谢谱的影响以确定其抗肥胖和 抗糖尿病功效。此外，正常血糖-高胰岛素钳夹结合离体分析， 将进行外周组织检查，以检查EA对胰岛素作用、脂肪代谢和 基因工程。将进行免疫组织化学分析胰岛β细胞质量和功能。 此外，口服生物利用度，代谢和潜在的毒性EA将进行研究。最后，小鼠模型， T2 D将用于研究EA加二甲双胍联合治疗的协同代谢效应。目的 2将确定EA抑制食物摄入和防止肥胖的机制。第一，影响 将评价EA对小鼠摄食反应和胃排空的影响，然后进行体外分析， 控制食物摄入的下丘脑通路。接下来，配对喂养结合能量消耗 将进行分析，以检查EA的抗肥胖功效在多大程度上是由减少的 能量摄入此外，脑室内给予靶向GLP-1的药理学抑制剂 受体（GLP-1 R）或PYY受体（Y2 R）以及受体缺失小鼠将用于研究 电针抑制摄食需要中枢PYY/Y2 R和/或GLP-1/GLP-1 R信号系统。结果 该项目的研究人员预计将确定一种治疗糖尿病和肥胖症的新型化合物的功效 以及揭示这些影响的机制，这将可能导致开发新的， 治疗糖尿病和肥胖症的安全有效的方法。

Project Summary Despite the wide application of commonly used drugs for type 2 diabetes (T2D) treatment, the prevalence of T2D continues to rise in the US. Insulin resistance and progressive decline in functional β-cell mass are two key driving forces for T2D. Obesity is a leading pathogenic factor for developing T2D, which is a significant obstacle for effective glycemic control in many patients with T2D. Thus, identifying novel agents that can simultaneously ameliorate obesity and promote insulin sensitivity and β-cell function would be a more effective strategy for preventing and treating T2D. In searching for agents with both anti-obesity and anti-hyperglycemic activities, we found for the first time that elenolic acid (EA), a small molecule generated from hydrolyzing olive leaf-derived oleuropein, is such a highly promising compound. Excitingly, oral administration of EA reversed hyperglycemia while also promoting weight loss and suppressing food intake in obese diabetic mice, Notably, EA was more effective in managing hyperglycemia and obesity than that of metformin. Interestingly, EA induced peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion from intestinal L-cells. In this grant, we propose to test hypothesis that EA is a dual acting agent for simultaneous treatment of obesity and diabetes via triggering PYY and GLP-1 secretion. Aim 1 will characterize the anti-diabetic and anti-obesity effects of EA. In that regard, diet- induced obese mice and obese diabetic db/db mice will receive EA treatment once daily via oral gavage. The effects of EA on metabolic profiles of obese diabetic mice will be examined for determining its anti-obesity and anti-diabetic efficacy. In addition, euglycemic-hyperinsulinemic clamps in combination with ex vivo analyses of peripheral tissues will be performed to examine the effects of EA on insulin action, fat metabolism, and gluconeogenic programs. Immunohistochemistry will be carried out to analyze Islet β-cell mass and function. Further, oral bioavailability, metabolism, and potential toxicity of EA will be studied. Lastly, mouse models with T2D will be used to investigate the synergistic metabolic effects of EA plus metformin combination therapy. Aim 2 will identify the mechanisms by which EA suppresses food intake and protects against obesity. First, the effects of EA on feeding responses and stomach emptying in mice will be evaluated, followed by ex vivo analyses of hypothalamic pathway controlling food intake. Next, pair-feeding in combination with energy expenditure analyses will be performed to examine the extent to which the anti-obesity efficacy of EA is driven by reduced energy intake. Additionally, intracerebroventricular administration of pharmacological inhibitors targeting GLP-1 receptor (GLP-1R) or PYY receptor (Y2R) as well as the receptor null mice will be used to investigate whether EA inhibition of food intake requires the central PYY/Y2R and/or GLP-1/GLP-1R signaling systems. The results of this project are expected to defining the efficacy of a novel compound for treating both diabetes and obesity as well as uncovering the mechanism underpinning these effects, which will potentially lead to developing new, safe, and effective therapy for battling both diabetes and obesity.