Mechanisms of drug side effects related to obesity and diabetes

肥胖和糖尿病相关药物副作用的机制

• 批准号: 8146903
• 负责人: CHRISTOPHER JOHN LYNCH
• 金额: $ 31.74万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146903
• 关键词: Acetyl-CoA Carboxylase; Address; Adult; Adverse drug effect; Adverse effects; Affect; Animal Model; Animals; Antipsychotic Agents; Body Weight; Cells; Child; Chronic; Citric Acid Cycle; Clinical; Comorbidity; Data; Deposition; Diabetes Mellitus; Drug usage; Eating; Event; Fatty acid glycerol esters; Feeding behaviors; Female; Food deprivation (experimental); Generations; Glucose; Goals; Heart; Human; Hunger; Hyperglycemia; Hypothalamic structure; Impairment; In Vitro; Incidence; Insulin Resistance; Knock-out; Leptin; Lipids; Lipolysis; Malonyl Coenzyme A; Mental disorders; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Muscle; Nonesterified Fatty Acids; Obesity; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Plasma; Prevalence; Rattus; Research; Rodent Model; Role; Schizophrenia; Skeletal Muscle; Testing; Therapeutic Intervention; Tissues; Triglycerides; Weight Gain; Work; acylcarnitine; atypical antipsychotic; design; enzyme pathway; experience; flexibility; in vitro Assay; in vivo; insulin sensitivity; interest; lipid metabolism; male; new therapeutic target; next generation; novel strategies; obesity treatment; olanzapine; oxidation; public health relevance; respiratory; sudden cardiac death; uptake

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. PUBLIC HEALTH RELEVANCE: Atypical antipsychotics are drugs used for psychiatric disorders like schizophrenia. While very effective in treating the psychiatric disorders, they inadvertently cause diabetes and obesity in the patients that have to take them. The number of adults and children using these drugs is increasing. So it is very important that we determine how these side effects occur so that we can alleviate them, so new drugs can be developed with reduced side effects. The studies we propose in animal models and cells will help identify factors underlying these effects. Another potential benefit of this research is that we may discover new targets for the treatment of obesity and diabetes. !

描述（由申请人提供）：该提案的长期目标是阐明用于治疗精神分裂症等精神疾病和其他精神疾病的非典型抗精神病药物（例如奥氮平）的代谢副作用机制。在过去 15 年里，成人和儿童的使用量急剧增加。这是有问题的，因为服用这些药物的患者经常出现严重的代谢副作用，包括肥胖、代谢综合征、糖尿病和心源性猝死。我们假设这些影响之前是中间代谢和脂质代谢的因果变化，这些变化导致胰岛素抵抗、饥饿、肥胖和肥胖合并症。有趣的初步数据表明，非典型抗精神病药会迅速而强烈地增加雄性和雌性大鼠和小鼠的脂肪氧化并损害代谢灵活性。我们认为，这种外围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和产生它所需的回补前体，这表明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胰岛素敏感性的组织特异性差异。最后，我们和其他人证明，在啮齿动物模型中，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/习惯活动减少的情况下维持不适当的治疗前食物摄入量有关。这些令人兴奋的发现所提出的问题将在以下具体目标中得到解决。目标 1：阐明代谢不灵活在非典型抗精神病药副作用中的作用，测试减轻这种副作用的策略，开发快速非侵入性体内或体外测定法来预测新兴第三代化合物代谢副作用的可能性并确定潜在机制。目标 2：确定奥氮平和其他抗精神病药物将能量捕获在脂肪中的机制。目标 3：检查摄入行为、下丘脑丙二酰辅酶 A 和瘦素在非典型抗精神病药物引起食欲的副作用中的作用。我们将利用生理学、分子学和药理学方法来揭示非典型抗精神病药物代谢副作用的机制，并测试逆转这些副作用的新策略。这项工作结束时，我们将开发出一种方法，可以在新兴化合物在人体进行测试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减少的下一代药物，并可能揭示治疗肥胖和糖尿病的新治疗靶点。 公共卫生相关性：非典型抗精神病药是用于治疗精神分裂症等精神疾病的药物。虽然它们在治疗精神疾病方面非常有效，但它们无意中导致必须服用它们的患者出现糖尿病和肥胖。使用这些药物的成人和儿童人数正在增加。因此，确定这些副作用是如何发生的非常重要，这样我们就可以减轻它们，从而可以开发出副作用更少的新药。我们在动物模型和细胞中提出的研究将有助于确定这些影响背后的因素。这项研究的另一个潜在好处是我们可能会发现治疗肥胖和糖尿病的新靶点。 ！