CNS Action of Appetite Suppressant Aminosterol

描述（由申请人提供）：肥胖在美国的患病率已经达到流行病的程度，并对公共卫生构成了巨大的挑战，因为肥胖是2型糖尿病、高血压、心血管疾病和癌症的主要危险因素，也是死亡的独立危险因素。尽管饮食和运动对体重管理至关重要，但越来越明显的是，很大一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，我们发现通过外周和更有效的脑室内注射给啮齿动物，可以引起可逆性的食物摄入抑制，能量消耗增加和葡萄糖水平正常化。与其他厌食症药物不同，单次注射MSI-1436可产生持续数天的长效效果。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，表明瘦素信号对其作用并不重要。相比之下，MSI-1436在豚鼠（Ay/a）小鼠中的作用减弱，表明其中枢作用可能涉及黑素皮质素途径。虽然急性给药MSI1436强烈诱导室旁核的fos免疫反应性，并在较小程度上诱导弓形核、腹内侧核和乳状前核的fos免疫反应性，但介导MSI-1436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通过一种特定的运输机制进入大脑，并参与下丘脑神经元靶点来调节能量平衡和葡萄糖稳态。特异性目的1涉及将MSI-1436注射到特定的下丘脑核，以确定哪些部位介导对摄食、体重和葡萄糖水平的影响。Specific Aim 2将分析MSI-1436结合位点的分布，并确定01个MSI-1436反应神经元的化学表型。特异性Aim 3将通过分析MSI-1436在黑素皮质素受体(MCR)-3和4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，Specific Aim 4将利用基因芯片来确定MSI-1436是否调控新的下丘脑基因。假定的MS-1436靶点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见解。了解MSI-1436对摄食行为、体重和葡萄糖的新影响的基础，将极大地促进肥胖和代谢领域的研究。受MSI-1436影响的新途径可能阐明肥胖治疗的新细胞靶点。

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.