CNS Action of Appetite Suppressant Aminosterol

描述（由申请人提供）：肥胖在美国的患病率已达到流行病的比例，并构成巨大的公共卫生挑战，因为肥胖是2型糖尿病、高血压、心血管疾病和癌症的主要风险因素，也是死亡的独立风险因素。虽然饮食和运动对体重管理至关重要，但越来越清楚的是，大部分患者需要药物治疗来降低和维持体重。这项资助的目的是了解一种具有有效抗肥胖和抗糖尿病特性的新型胆固醇衍生物的作用。MSI- 1436是一种氨基甾醇，我们发现当通过外周和更有效的脑室内注射给啮齿动物施用时，其引起食物摄入的可逆抑制、能量消耗增加和葡萄糖水平正常化。与其他厌食剂不同，MSI-1436的单次注射产生持续数天的长期效果。MSI- 1436在ob/ob和db/db小鼠、fa/fa大鼠和饮食诱导的肥胖小鼠中有效，表明瘦素信号传导对其作用并不关键。相比之下，MSI-1436的作用是钝的agglutinase（Ay/a）小鼠，表明其中枢作用可能涉及黑皮质素途径。尽管急性MSI 1436给药强烈诱导室旁核中的Fos免疫反应性，并且在弓状核、腹内侧核和乳头体前核中诱导Fos免疫反应性的程度较低，但介导MSI-1436的抗肥胖与抗糖尿病作用的神经元回路尚不清楚。我们假设MSI-1436通过特定的转运机制进入大脑，并与下丘脑神经元靶点结合以调节能量平衡和葡萄糖稳态。具体目标1涉及将MSI-1436注射到特定的下丘脑核中，以确定哪些位点介导对进食、体重和葡萄糖水平的影响。具体目标2将分析MSI-1436结合位点的分布，并确定MSI-1436反应神经元的化学表型。具体目标3将通过分析黑皮质素受体（MCR）-3和4敲除小鼠中的MSI-1436应答来确定中枢黑皮质素系统的贡献。最后，具体目标4将利用基因芯片芯片，以确定是否MSI-1436调节新的下丘脑基因。将在多个小鼠模型中验证推定的MS-1436靶标。这些研究将为MSI-1436在大脑中的作用机制提供见解。了解MSI-1436对进食行为、体重和葡萄糖的新作用的基础将大大增强肥胖和代谢领域。受MSI-1436影响的新途径可能阐明治疗肥胖症的新细胞靶点。

DESCRIPTION (provided by applicant): The prevalence of obesity in the United States has reached epidemic proportions and poses enormous public health challenges, as obesity is a major risk factor for type 2 diabetes, hypertension, cardiovascular disease and cancer, as well as an independent risk factor for mortality. Although diet and exercise are essential to weight management, it has become increasingly clear that a large proportion of patients would require drug treatment to decrease and maintain body weight. The goal of this grant is to understand the action of a novel cholesterol derivative with potent anti-obesity and anti-diabetic properties. MSI- 1436 is an aminosterol which we have found to cause reversible suppression of food intake, increased energy expenditure and normalization of glucose levels when administered by peripheral and more potently intracerebroventricular injection to rodents. Unlike other anorectics, a single injection of MSI-1436 produces a prolonged effect lasting several days. MSI- 1436 is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice, suggesting that leptin signaling is not critical to its action. By contrast, MSI-1436 effect is blunted in agouti (Ay/a) mice, suggesting that its central action may involve the melanocortin pathway. Although acute MSI1436 administration strongly induces Fos-immunoreactivity in the paraventricular nucleus and to a lesser extent in the arcuate, ventromedial and pre-mammillary nuclei, the neuronal circuitry mediating the anti-obesity vs anti-diabetic effects of MSI-1436 is not known. We hypothesize that MSI-1436 enters the braii via a specific transport mechanism and engages hypothalamic neuronal targets to regulate energy balance and glucose homeostasis. Specific Aim 1 involves the injection of MSI-1436 into specific hypothalamic nuclei to determine which sites mediate the effects on feeding, body weight and glucose levels. Specific Aim 2 will analyze the distribution of MSI-1436 binding sites and determine the chemical phenotypes 01 MSI-1436 responsive neurons. Specific Aim 3 will determine the contribution of the central melanocortin system by analyzing MSI-1436 response in melanocortin receptor (MCR)-3 and 4 knockout mice. Finally, Specific Aim 4 will utilize GeneChip microarray to determine whether MSI-1436 regulates novel hypothalamic genes. Putative MS-1436 targets will be validated in multiple mouse models. Together these studies will provide insights into the mechanisms underlying MSI-1436 action in the brain. Understanding the basis for the novel effects of MSI-1436 on feeding behavior, body weight and glucose will greatly enhance the field of obesity and metabolism. New pathways affected by MSI-1436 may elucidate novel cellular targets for the treatment of obesity.