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

项目摘要 尽管治疗2型糖尿病(T2D)的常用药物得到广泛应用，但 T2D在美国继续上升。胰岛素抵抗和功能性β细胞质量进行性下降是两个关键 T2D的驱动力。肥胖是导致T2D的主要致病因素，而T2D是一个重要的障碍 用于有效控制许多T2D患者的血糖。因此，识别可以同时 改善肥胖，促进胰岛素敏感性和β细胞功能将是一种更有效的策略 预防和治疗T2D。在寻找同时具有抗肥胖和抗高血糖活性的药物时，我们 首次发现橄榄叶水解产生的小分子烯酸(EA)来源于 橄榄苷，是一种非常有前途的化合物。令人兴奋的是，口服EA可逆转高血糖 在促进肥胖糖尿病小鼠体重减轻和抑制食物摄入的同时，值得注意的是，电针的 在控制高血糖和肥胖方面比二甲双胍有效。有趣的是，电针诱导的多肽YY 肠L细胞分泌胰升糖素样肽-1(GLP-1)。在这笔赠款中，我们建议测试 电针是通过触发PYY同时治疗肥胖和糖尿病的双重作用剂的假说 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- 诱导肥胖小鼠和肥胖糖尿病db/db小鼠将接受电针治疗，每天一次，通过口服。这个 研究电针对肥胖糖尿病小鼠代谢的影响，以确定电针的抗肥胖和抗肥胖作用。 抗糖尿病功效。此外，正常血糖-高胰岛素钳夹结合体外分析 将进行外周组织检查，以检查电针对胰岛素作用、脂肪代谢和 糖异生计划。用免疫组织化学方法分析胰岛β细胞的质量和功能。 此外，还将研究EA的口服生物利用度、代谢和潜在毒性。最后，鼠标模型与 T2D将用于研究电针加二甲双胍联合治疗的协同代谢效应。目标 2将确定电针抑制食物摄取和预防肥胖的机制。首先，影响 将评估电针对小鼠的摄食反应和胃排空的影响，随后将进行体外分析 控制食物摄取的下丘脑通路。其次，配对喂养与能量消耗相结合 将进行分析，以检查电针的减肥效果在多大程度上是由减少 能量摄入。此外，脑室内给药靶向GLP-1的抑制剂 受体(GLP-1R)或PYY受体(Y2R)以及受体缺失的小鼠将被用于研究 电针抑制食物摄取需要中枢PYY/Y2R和/或GLP-1/GLP-1R信号系统。结果是 预计将确定一种治疗糖尿病和肥胖症的新化合物的疗效 以及揭示支撑这些效应的机制，这可能会导致开发新的， 与糖尿病和肥胖作斗争的安全、有效的疗法。

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.