CNS Action of Appetite Suppressant Aminosterol

描述(申请人提供)：肥胖症在美国的流行程度已经达到流行病的程度，并对公共卫生构成巨大的挑战，因为肥胖症是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。虽然饮食和锻炼对体重控制是必不可少的，但越来越明显的是，很大一部分患者需要药物治疗来减轻和保持体重。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，我们已经发现，当通过外周和更有效的脑室内注射给药给药时，它可以引起可逆性的食物摄取抑制、能量消耗增加和血糖水平正常化。与其他厌食药不同的是，一次注射MSI-1436就能产生持续数天的持久效果。MSI-1436对ob/ob和db/db小鼠、FA/FA大鼠和饮食诱导的肥胖小鼠有效，这表明瘦素信号对其作用不是关键。相反，MSI-1436的作用在刺鼠(Ay/a)小鼠中是钝化的，这表明它的中枢作用可能涉及黑素皮质素途径。尽管急性给予MSI1436在室旁核有强烈的Fos免疫反应，在弓状核、腹内侧核和乳头体前核也有少量的Fos免疫反应，但MSI-1436的抗肥胖和抗糖尿病作用的神经元回路尚不清楚。我们假设MSI-1436通过一种特定的转运机制进入大脑，并与下丘脑神经元靶点结合来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团中，以确定哪些位置介导了对摄食、体重和血糖水平的影响。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MSI-1436在黑素皮质素受体(MCR)-3和4基因敲除小鼠中的反应来确定中枢黑素皮质素系统的贡献。最后，特殊目标4将利用基因芯片微阵列来确定MSI-1436是否调控新的下丘脑基因。假定的MS-1436靶子将在多个小鼠模型中进行验证。总之，这些研究将为MSI-1436在大脑中的作用机制提供深入的见解。了解MSI-1436对进食行为、体重和葡萄糖的新影响的基础将极大地促进肥胖和新陈代谢领域的研究。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.