Ginsenocide Rb1: A Novel Anti-Obesity and Anti-Hyperglycemic Compound

描述(申请人提供)：肥胖和2型糖尿病是全国性和世界性的流行病。由于目前可用的抗肥胖和抗糖尿病药物的疗效有限，而且存在安全性问题，因此寻找新的靶向化合物，特别是具有控制体重和血糖双重特性的化合物，是当务之急。最近，我们发现了人参皂苷Rb1(Rb1)的新功能，人参皂苷Rb1是人参中含量最丰富、活性最强的化合物。数千年来，人参在亚洲国家一直被用作恢复和增进健康的传统生药，没有明显的毒副作用，是美国最畅销的草药补充剂之一。给大鼠外周注射Rb1可以有效地抑制食物摄入量，而不会引起毒性迹象。Rb1的长期治疗显著减少了高脂饮食(HFD)诱导的肥胖大鼠的食物摄入量和体重增加，也显著降低了空腹血糖，并在更大程度上改善了糖耐量受损的情况。这些结果表明Rb1作为一种抗肥胖和抗高血糖药物具有潜在的新作用。我们的中心假设是，Rb1增加了瘦素的敏感性，以维持身体能量和葡萄糖的动态平衡，这一假设得到了我们在瘦身和高脂诱导的肥胖大鼠中的初步数据的有力支持。这项拟议研究的基本原理是，一旦了解了Rb1调节体重和血糖的特殊机制，新获得的信息将允许合理设计未来的临床前研究和临床试验，以开发Rb1作为预防和治疗肥胖和糖尿病的新药物。在强劲的初步数据的指导下，我们建议通过追求三个具体目标来检验这一假说。首先，确定Rb1和瘦素在减少大鼠摄食量中的相互作用。第二，确定Rb1改善高脂诱导的肥胖大鼠能量稳态的机制。第三，验证Rb1和瘦素一样，通过增加外周组织的胰岛素敏感性和/或通过增加胰岛素分泌来调节葡萄糖代谢的假设。这项拟议的工作具有创新性，因为它评估了Rb1在调节能量和葡萄糖动态平衡方面的新药理功能。这项拟议研究的成功完成将增强我们对Rb1预防和治疗肥胖症及其相关代谢综合征症状的机制的理解。鉴于肥胖和糖尿病的持续流行，寻找和了解一种具有控制体重和降低血糖双重特性的新型药理制剂，如Rb1，预计将对公众健康产生重大影响。

DESCRIPTION (provided by applicant): Obesity and type-2 diabetes are national and worldwide epidemics. Since currently available anti-obesity and anti-diabetes drugs have limited efficacy as well as safety concerns, identifying new target compounds, particularly with dual properties in controlling both body weight and blood glucose, is a high priority. Recently, we have identified novel functions of ginsenoside Rb1 (Rb1), the most abundant and biologically active compound in ginseng. Ginseng has been used as a traditional crude medicine in Asian countries to restore and enhance well-being without notable toxic side effects for thousands of years, and is one of the best-selling herbal supplements in the United States. Peripheral administration of Rb1 to rats potently suppresses food intake without eliciting signs of toxicity. Chronic treatment with Rb1 significantly reduces food intake and body weight gain in high-fat diet (HFD)-induced obese rats and also significantly decreases fasting blood glucose and improves impaired glucose tolerance to a greater extent than what occurs in pair-fed controls. These results demonstrate potential novel roles for Rb1 as an anti-obesity and anti-hyperglycemic agent. Our central hypothesis is that Rb1 increases leptin sensitivity to maintain body energy and glucose homeostasis, and it is strongly supported by our preliminary data in lean and HFD-induced obese rats. The rationale for the proposed research is that once the particular mechanisms of Rb1 in the regulation of body weight and blood glucose are understood, the newly acquired information will allow rational design of future pre-clinical studies and clinical trials to develop Rb1 as a novel agent for the prevention and treatment of obesity and diabetes. Guided by strong preliminary data, we propose testing this hypothesis by pursuing three specific aims. First, to determine the interaction of Rb1 and leptin in reducing food intake in rats. Second, to identify the mechanisms through which Rb1 improves energy homeostasis in HFD-induced obese rats. Third, to test the hypothesis that Rb1, like leptin, regulates glucose metabolism by increasing insulin sensitivity at peripheral tissues and/or by increasing insulin secretion. The proposed work is innovative because it assesses novel pharmacological functions of Rb1 in the regulation of energy and glucose homeostasis. Successful completion of the proposed research will enhance our understanding of the mechanisms by which Rb1 prevents and treats obesity and associated symptoms of the metabolic syndrome. Given the continuing epidemics of obesity and diabetes, identifying and understanding a novel pharmacological agent, such as Rb1, with the dual properties of controlling body weight and reducing blood glucose, is expected to have a significant public health impact.