Mechanisms of drug side effects related to obesity and diabetes

描述（由申请人提供）：本提案的长期目标是阐明用于治疗精神分裂症和其他精神疾病的非典型抗精神病药物（如奥氮平）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。这是一个问题，因为服用这些药物的患者经常出现肥胖、代谢综合征、糖尿病、心脏性猝死等严重的代谢副作用。我们假设这些影响是由驱动胰岛素抵抗、饥饿、肥胖和肥胖合并症的中间代谢和脂质代谢的因果变化引起的。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和损害代谢灵活性。我们认为，这种不适当的外周燃料利用转换为脂质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和产生它所需的复变前体，这提示了逆转这些代谢副作用的机制和策略。值得注意的是，合成丙二醇辅酶a或受其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胰岛素敏感性的组织特异性差异。最后，我们和其他人已经表明，在啮齿类动物模型中，非典型抗精神病药物引起的体重增加和肥胖部分与食物摄入量增加或在身体/习惯性活动减少的情况下维持不适当的预处理食物摄入量有关。这些令人兴奋的发现提出的问题将在以下具体目标中加以解决。目的1：阐明代谢不灵活性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，开发一种快速的非侵入性体内或体外试验，以预测新出现的第三代化合物代谢副作用的可能性，并确定其潜在机制。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3：检查摄取行为，下丘脑丙二醇辅酶a和瘦素在非典型抗精神病药物的缺氧副作用中的作用。生理学、分子和药理学方法将用于揭示非典型抗精神病药物代谢副作用的机制，我们将测试新的策略来逆转它们。通过这项工作的结论，我们将开发出一种方法，在对新化合物进行人体试验之前，快速预测其与肥胖相关的副作用的可能性。这将有助于设计副作用更小的下一代药物，也可能揭示治疗肥胖和糖尿病的新治疗靶点。

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.