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

描述（由申请人提供）：肥胖和 2 型糖尿病是全国和世界范围内的流行病。由于目前可用的抗肥胖和抗糖尿病药物的功效有限且存在安全性问题，因此识别新的目标化合物，特别是具有控制体重和血糖的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 是人参中最丰富且具有生物活性的化合物。数千年来，人参一直被亚洲国家用作恢复和增强健康的传统生药，且没有明显的毒副作用，并且是美国最畅销的草药补充剂之一。对大鼠进行外周注射 Rb1 可有效抑制食物摄入，且不会引起毒性迹象。与配对喂养对照组相比，长期使用 Rb1 治疗可显着减少高脂饮食 (HFD) 诱导的肥胖大鼠的食物摄入量和体重增加，并且还显着降低空腹血糖并改善糖耐量受损。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，并且我们在瘦大鼠和 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殊机制，新获得的信息将有助于合理设计未来的临床前研究和临床试验，将Rb1开发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检验这一假设。首先，确定 Rb1 和瘦素在减少大鼠食物摄入中的相互作用。其次，确定 Rb1 改善 HFD 诱导的肥胖大鼠能量稳态的机制。第三，检验 Rb1 与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 在能量和葡萄糖稳态调节中的新药理功能。成功完成拟议的研究将增强我们对 Rb1 预防和治疗肥胖及代谢综合征相关症状的机制的理解。鉴于肥胖和糖尿病的持续流行，识别和了解一种新型药物制剂，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.