CNS action of appetite suppressant aminosterol

描述(由申请人提供)：肥胖症的流行与不断增加的 糖尿病、心血管疾病等并发症的发生率。饮食和锻炼对体重管理是必不可少的；然而，很明显，许多患者需要药物治疗才能实现并保持体重减轻。这项资助的目的是了解一种新的氨基类固醇的作用，我们已经发现它可以有效地减轻体重。在过去的三年中，我们已经证明MSI-1436的减肥作用是通过抑制食物摄入和增加代谢率来实现的。与其他厌食药不同，单一的腹膜内或脑室内(i.c.v.)注射MSI-1436可以连续几天减轻体重。此外，MSI-1436刺激胰岛素反应，防止脂肪变性。完整的瘦素信号对MSI-1436的作用不是关键，因为这种化合物对ob/ob和db/db小鼠、fa/fa大鼠和饮食诱导的肥胖小鼠有效。相比之下，刺鼠(Ay/a)对MSI-1436的反应较差，这表明黑素皮质素(MC)3/4受体对其在大脑中的作用至关重要。MSI-1436与下丘脑和其他调节能量平衡的脑区结合，在下丘脑室旁核强烈诱导Fos免疫反应，在弓状核、腹内侧核、中央杏仁核和孤束核也有少量的Fos免疫反应。MSI-1436对下丘脑中刺鼠相关肽(AGRP)和神经肽Y(NPY)的抑制进一步证明了MSI-1436的中枢作用。因此，我们假设MSI-1436通过类似的下丘脑回路来调节能量平衡和血糖。具体目标1将调查NPY或AGRP治疗是否可以逆转MSI-1436的作用。此外，我们还将 确定NPY、AGRP和MC4受体基因的缺失是否阻断MSI-1436的作用。 特异性目标2将研究NPY、AGRP和MC4受体在MSI-1436对血糖的影响中的作用。具体目标3将评估MSI-1436对下丘脑酶，即AMP激酶和脂肪酸合成酶的影响，这些酶与能量平衡有关。最后，特定的目标4将确定下丘脑AMP激酶的激活是否能够阻止MSI-1436的作用，正如已经在各种厌食剂中所显示的那样。了解MSI-1436的中枢神经活动可能会阐明治疗肥胖和相关疾病的新靶点。

DESCRIPTION (provided by applicant): The obesity epidemic has been linked to increasing incidence of diabetes, cardiovascular disease and other complications. Diet and exercise are essential to weight management; however, it is obvious that many patients would require drug treatment to achieve and maintain weight reduction. The goal of this grant is to understand the actions of a novel aminosterol, which we have found to potently decrease body weight. During the past 3 years, we have shown that the anti-obesity effect of MSI-1436 is mediated through inhibition of food intake as well as increased metabolic rate. Unlike other anorectics, a single intraperitoneal or intracerebroventricular (i.c.v.) injection of MSI-1436 decreases body weight for several days. Moreover, MSI-1436 stimulates insulin response and prevents steatosis. An intact leptin signaling is not critical to the action of MSI-1436, since this compound is effective in ob/ob and db/db mice, fa/fa rats, and diet-induced obese mice. In contrast, agouti (Ay/a) mice are less responsive to MSI-1436, suggesting that melanocortin (MC)3/4 receptors are crucial its action in the brain. MSI-1436 binds to hypothalamic and other brain areas which mediate energy balance, and strongly induces Fos-immunoreactivity in the paraventricular hypothalamic nucleus and to a lesser extent in the arcuate, ventromedial nuclei, central amygdala and nucleus solitarius. A CNS action of MSI-1436 is further evident by the suppression of agouti-related peptide (AGRP) and neuropeptide Y (NPY) in hypothalamus. Hence, we hypothesize that MSI-1436 regulates energy balance and glucose through similar hypothalamic circuits. Specific Aim 1 will investigate whether treatment with NPY or AGRP can reverse the effect of MSI-1436. Moreover, we will determine whether deletion of NPY, AGRP and MC4 receptor genes block the action of MSI-1436. Specific Aim 2 will investigate the roles of NPY, AGRP and MC4 receptor in mediating the effect of MSI-1436 on glucose. Specific Aim 3 will evaluate the effects of MSI-1436 on hypothalamic enzymes, i.e. AMP kinase and fatty acid synthase, implicated in energy homeostasis. Finally, specific Aim 4 will determine whether activation of hypothalamic AMP kinase is able to prevent the effect of MSI-1436, as has been shown for various anorectics. Understanding of the central neuronal actions MSI-1436 may elucidate novel targets for the treatment of obesity and related diseases.