Mechanisms of drug side effects related to obesity and diabetes

描述(申请人提供)：这项提案的长期目标是阐明非典型抗精神病药物(如奥氮平)用于治疗精神分裂症和其他精神障碍等精神障碍的代谢副作用的机制。在过去的15年里，成人和儿童对它们的使用急剧增加。这是有问题的，因为服用这些药物的患者经常会出现严重的代谢副作用，包括肥胖、代谢综合征、糖尿病和心脏性猝死。我们假设，在这些效应之前，中间体和脂代谢的因果变化会导致胰岛素抵抗、饥饿、肥胖和肥胖并存。有趣的初步数据显示，非典型抗精神病药物迅速而有力地增加了雄性和雌性大鼠和小鼠的脂肪氧化并损害了代谢灵活性。我们认为，这种外周燃料利用向脂质的不适当转换是通过兰德尔循环效应导致胰岛素抵抗的原因。这种燃料转换可能涉及降低骨骼肌丙二酰辅酶A和产生丙二酰辅酶A所需的停滞前体，这表明了一种逆转这些代谢副作用的机制和策略。值得注意的是，合成丙二酰辅酶A或受丙二酰辅酶A影响的酶和途径的组织特异性表达可以解释奥氮平引起的组织特异性胰岛素敏感性差异。最后，我们和其他人已经证明，在啮齿动物模型中，非典型抗精神病药物导致的体重增加和肥胖部分与增加食物摄入量或在身体/习惯活动减少的情况下保持不适当的预处理食物摄入量有关。提出的问题这些令人振奋的调查结果将在以下具体目标中得到解决。目的1：阐明代谢不灵活在非典型抗精神病药物副作用中的作用，测试减轻这种副作用的策略，建立一种快速、非侵入性的体内或体外试验，以预测新出现的第三代化合物代谢副作用的可能性，并确定潜在的机制。目的2：确定奥氮平和其他抗精神病药物在脂肪中捕获能量的机制。目的：研究进食行为、下丘脑丙二酰辅酶A和瘦素在非典型抗精神病药物食欲不良反应中的作用。生理学、分子和药理学方法将被用来揭示非典型抗精神病药物代谢副作用的潜在机制(S)，我们将测试逆转这些副作用的新策略。通过这项工作的结论，我们将开发出一种方法，在对人体进行测试之前，快速预测新出现的化合物中与肥胖相关的副作用的可能性。这将有助于设计副作用减少的下一代药物，并可能揭示治疗肥胖症和糖尿病的新治疗目标。

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to elucidate the mechanisms of the metabolic side effects of atypical antipsychotics (e.g., olanzapine) that are used to treat psychiatric disorders like schizophrenia and other psychiatric disorders. Over the last 15 years their use has grown sharply in adults and children. This is problematic because patients taking take these drugs are frequented by serious metabolic side effects including obesity, metabolic syndrome, diabetes and sudden cardiac death. We hypothesize that these effects are preceded by causal changes in intermediary and lipid metabolism that drive the insulin resistance, hunger, adiposity and obesity-comorbidities. Interesting preliminary data shows that atypical antipsychotics rapidly and robustly increase fat oxidation and impair metabolic flexibility in male and femal rats and mice. We propose that this inappropriate switching of peripheral fuel utilization to lipid is what leads to insulin resistance via a Randle cycle effect. This fuel switching may involve lowering of skeletal muscle malonyl-CoA and anaplerotic precursors needed to produce it, suggesting a mechanism and strategies for reversing these metabolic side effects. Notably the tissue specific expression of enzymes and pathways that synthesize or are affected by malonyl CoA could explain the tissue specific differences in insulin sensitivity caused by olanzapine. Finally we and others have shown that the weight gain and adiposity caused by atypical antipsychotics in rodent models is associated in part with either increased food intake or maintaining an inappropriate pretreatment food intake in the context of decreased physical/habitual activity. Questions raised these exciting findings will be addressed in the following specific aims. Aim 1: Elucidate the role of metabolic inflexibility in the side effects of atypical antipsychotics, test strategies to alleviate this side effect, develop a rapid non-invasive in vivo or in vitro assay to predict likelihood of metabolic side effects in emerging third generation compounds and determine the underlying mechanisms. Aim 2: Determine the mechanisms underlying trapping of energy in fat by olanzapine and other antipsychotics. Aim 3: Examine the role of ingestive behavior, hypothalamic malonyl- CoA and leptin in the orexigenic side effects of atypical antipsychotics. Physiological, molecular and pharmacological approaches will be used to reveal the mechanism(s) underlying the metabolic side effects of atypical antipsychotics and we will test novel strategies to reverse them. By the conclusion of this work, we will have developed an approach to rapidly predict the likelihood of obesity-related side effects in emerging compounds before they are tested in humans. This will aid in the design of next generation drugs with reduced side effects and may also reveal new therapeutic targets for the treatment of obesity and diabetes.