Pregnane and Glycosides and Obesity/llya Raskin

体重失调背后的许多病理生理机制可以通过调节能量稳态中的中心调节元件来控制，包括食物摄入和能量消耗。尽管缺乏临床前、临床和毒理学研究证据，但含有从沙漠马利筋植物Hoodia中提取的富含孕苷的膳食补充剂是最受欢迎的植物性减肥疗法之一。为了验证富含孕酮苷的植物制剂的生理和药理作用，我们筛选了乳草科植物，并确定了沼泽乳草，Asclepias incarnata，一种常见的快速生长的北美亲戚，作为活性成分的替代来源。牛角莲提取物可显著减少食物摄入，减少脂肪沉积，改善胰岛素敏感性指标，这可能是通过初级迷走神经传入的肠脑交流机制实现的。研究包括用提取物进行慢性治疗和配对喂养，以控制其对食物摄入的影响，这支持了提取物独立于其对食物摄入的影响之外的额外代谢作用。基于这些观察，我们假设化身通过促进饱腹感和刺激能量消耗来影响能量稳态。因此，我们的主要目标是通过三个具体目标来了解这种植物增强饱腹感和减缓代谢综合征进展的机制的互补组成部分：1)确定化身控制食物摄入的作用部位和机制；2)确定能量消耗在动物抗肥胖活动中的作用机制；3)在受控条件下使用人类消化系统功能模型定义incarnatin及其生物活性成分的生物利用度，并使用细胞培养分析评估其结构-活性特性。

Many pathophysiological mechanisms that underlie weight disorders can be managed through modulation of central regulatory elements in energy homeostasis, including food intake and energy expenditure. Dietary supplements that contain pregnane glycoside-enriched extract from a desert milkweed plant Hoodia are among the most popular botanical weight-loss remedies despite the lack of pre-clinical, clinical, and toxicological research evidence. To validate the physiological and pharmacological effects of pregnane glycoside-enriched botanicals, we screened plants that belong to milkweed family and identified swamp milkweed, Asclepias incarnata, a common and fast growing North American relative of Hoodia, as an alternative source of active ingredients. A. incarnata extract produced an acute reduction in food intake that reduced fat deposition and improved markers of insulin sensitivity, possibly through a mechanism requiring gut-brain communication via primary vagal afferents. Studies involving chronic treatment with the extract and pair feeding to control for its effect on food intake supported an additional metabolic role ofthe extract independent of its effects on food intake. Based on these observations, we hypothesize that incarnatin impacts energy homeostasis by promoting satiety and stimulating energy expenditure. Thus our primary goal is to understand the complementary components ofthe mechanism(s) by which this botanical enhances satiety and attenuates the progression to metabolic syndrome through three specific aims: 1) To identify the site of action and mechanism(s) through which incarnatin controls food intake; 2) To determine the mechanisms of energy expenditure in the antiobesity activity of incarnatin; 3) To define bioavailability of incarnatin and its bioactive component(s) using a functional model ofthe human digestive system under controlled conditions and evaluate their structure-activity properties using cell culture assays.