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

描述（由申请人提供）：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，因此确定新的目标化合物，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。人参皂苷Rb1 （ginsenoside Rb1, Rb1）是人参中含量最高、最具生物活性的化合物。几千年来，人参一直被亚洲国家用作恢复和增强健康的传统药材，没有明显的毒副作用，是美国最畅销的草药补充剂之一。外周给药Rb1对大鼠有效地抑制食物摄入而不引起毒性迹象。用Rb1进行慢性治疗可以显著减少高脂肪饮食（HFD）诱导的肥胖大鼠的食物摄入量和体重增加，还可以显著降低空腹血糖，并在更大程度上改善糖耐量受损，而不是成对喂养的对照组。这些结果证明了Rb1作为抗肥胖和抗高血糖药物的潜在新作用。我们的中心假设是Rb1增加瘦素敏感性以维持身体能量和葡萄糖稳态，我们在瘦鼠和hfd诱导的肥胖大鼠中的初步数据有力地支持了这一假设。这项研究的基本原理是，一旦了解了Rb1调节体重和血糖的特定机制，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型药物。在强有力的初步数据的指导下，我们建议通过追求三个具体目标来验证这一假设。首先，确定Rb1和瘦素在减少大鼠食物摄入量中的相互作用。第二，确定Rb1改善hfd诱导的肥胖大鼠能量稳态的机制。第三，验证Rb1像瘦素一样，通过增加外周组织的胰岛素敏感性和/或增加胰岛素分泌来调节葡萄糖代谢的假设。这项工作具有创新性，因为它评估了Rb1在调节能量和葡萄糖稳态中的新药理功能。这项研究的成功完成将增强我们对Rb1预防和治疗肥胖及代谢综合征相关症状的机制的理解。鉴于肥胖症和糖尿病的持续流行，确定和了解一种新的药理学制剂，如Rb1，具有控制体重和降低血糖的双重特性，预计将对公共卫生产生重大影响。

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.