CNS action of appetite suppressant aminosterol

在过去的四年中，我们已经证明，氨基甾醇，MSI-1436，降低啮齿动物的体重 通过抑制食物摄入和增加产热作用。MSI-1436对饮食诱导的肥胖也有效 作为瘦素缺乏小鼠，并迅速降低血糖和刺激脂肪酸氧化，在这些 模型由于MSI-1436在注射到脑室和下丘脑时更有效， 室旁核，该化合物的药理作用可能直接发生在脑中。 事实上，我们已经证明了弓状核内MSI-1436的结合增加，并且抑制了MSI-1436的表达。 AGRP和NPY mRNA在小鼠中的表达，暗示表达这些神经肽的神经通路， MSI-1436目标。独立于体重减轻，MSI-1436改变了参与脂质代谢的酶的表达。 和葡萄糖代谢，如下丘脑AMP激酶（AMPK）和肝脂肪酸合成酶（FAS）。 此外，与野生型动物相比，agglutinase（Ay/a）小鼠对MSI-1436的敏感性较低，并且对MSI-1436的应答也较低。 MSI-1436被SHU 9119抑制，这与黑皮质素系统是一个关键的细胞因子的假设一致。 在MSI-1436的中枢作用模式中的通路。我们最近发现了一种小鼠下丘脑细胞 细胞系（GT 1 -7），其中亚微摩尔浓度的MSI-1436增强α-MSH的激动剂活性， 提示MSI-1436可能影响黑皮质素途径的可能机制。这 该提案将进一步探索MSI-1436通过中枢机制发挥作用的假设。目标1将评估 黑皮质素4受体（MC 4 R）的药理学阻断或基因缺失对黑皮质素4受体（MC 4 R）表达能力的影响。 MSI-1436通过下丘脑室旁核抑制摄食和刺激产热。我们 将探讨促肾上腺皮质激素释放激素（CRH）是否在MC 4 R下游起作用以介导这种效应 MSI-1436对摄食和产热的影响。目标2将试图解决MSI-1436 增强了体外结合和GT 1 -7下丘脑神经元中通过MC 4 R的信号传导。最后，Aim 3将 确定对葡萄糖和脂质代谢的快速作用是否通过MC 4 R介导， 下丘脑的AMPK。了解中枢神经元的行动MSI-1436将提供新的 对这种氨基甾醇的抗肥胖和胰岛素增敏作用的见解。

During the past four years, we have shown that an aminosterol, MSI-1436, decreases body weight in rodents by inhibiting food intake and increasing thermogenesis. MSI-1436 is effective in diet-induced obese as well as leptin-deficient mice, and rapidly decreases plasma glucose and stimulates fatty acid oxidation in these models. Since MSI-1436 is more potent when injected in the cerebral ventricle and into the hypothalamic paraventricular nucleus, it is likely that the pharmacologic effects of this compound occur directly in the brain. Indeed, we have shown increased binding of MSI-1436 within the arcuate nucleus, and suppression of AGRP and NPY mRNA expression in mice, implicating neural pathways expressing these neuropeptides as MSI-1436 targets. Independent of weight loss, MSI-1436 alters the expression of enzymes involved in lipid and glucose metabolism, such as hypothalamic AMP kinase (AMPK) and hepatic fatty acid synthase (FAS). Furthermore, agouti (Ay/a) mice are less sensitive than wild-type animals to MSI-1436 and the response to MSI-1436 is inhibited by SHU9119, consistent with the hypothesis that the melanocortin system is a critical pathway in the central mode of action of MSI-1436. We have recently identified a mouse hypothalamic cell line (GT1-7) in which MSI-1436, at submicromolar concentrations, enhanced the agonist activity of a-MSH, suggesting a possible mechanism by which MSI-1436 might influence the melanocortin pathway. This proposal will further explore the hypothesis that MSI-1436 acts via central mechanisms. Aim 1 will evaluate the effects of pharmacologic blockade or genetic deletion of melanocortin 4 receptor (MC4R) on the ability of MSI-1436 to inhibit feeding and stimulate thermogenesis via the hypothalamic paraventricular nucleus. We will explore whether corticotropin-releasing hormone (CRH) acts downstream of MC4R to mediate the effects of MSI-1436 on feeding and thermogenesis. Aim 2 will attempt to resolve the mechanism by which MSI-1436 enhances the in vitro binding and signaling via MC4R in GT1-7 hypothalamic neurons. Finally, Aim 3 will determine whether the rapid actions on glucose and lipid metabolism are mediated through MC4R and AMPK in the hypothalamus. Understanding of the central neuronal actions MSI-1436 will provide novel insights on the anti-obesity and insulin sensitizing actions of this aminosterol.