Hypothalamic MC4Rs and Antipsychotic Drug-Induced Metabolic Syndrome

下丘脑 MC4R 和抗精神病药物引起的代谢综合征

• 批准号: 10584208
• 负责人: Chen Liu
• 金额: $ 48.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584208
• 关键词: Acute; Affect; Agonist; Animal Model; Antipsychotic Agents; Attention deficit hyperactivity disorder; Behavioral; Binding; Brain region; Cells; Child; Chromatin; Chronic; Clinical; Data; Desire for food; Development; Diabetes Mellitus; Discipline; Drug Interactions; Drug Targeting; Drug usage; Dyslipidemias; Electrophysiology (science); Energy Intake; Etiology; Expenditure; FDA approved; Gene Expression; General Population; Genes; Genetic; Genetic Transcription; Genomics; Glucose Intolerance; Goals; Grant; Human; Hyperphagia; Hypothalamic structure; Impairment; Individual; Insulin Resistance; Kir7.1 channel; Knockout Mice; Laboratory Animals; Link; Mediating; Medicine; Melanocortin 4 Receptor; Messenger RNA; Metabolic; Metabolic syndrome; Modeling; Molecular; Morbid Obesity; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physical activity; Potassium; Potassium Channel; Research; Resources; Risperidone; Role; Schizophrenia; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Suggestion; Therapeutic; Time; United States National Institutes of Health; Weight Gain; Work; autism spectrum disorder; cell type; driving force; drug action; drug-induced weight gain; excessive weight gain; experimental study; improved; interdisciplinary approach; inward rectifier potassium channel; mouse model; neuropsychiatry; new therapeutic target; next generation; novel; obesogenic; olanzapine; paraventricular nucleus; postsynaptic; receptor; receptor expression; restoration; side effect; single nucleus RNA-sequencing; transcriptome; transcriptome sequencing

PROJECT SUMMARY Antipsychotic drug (APD)-induced metabolic syndrome is a pressing clinical problem affecting millions of patients. However, the difficulty in modeling their metabolic effects in laboratory animals has significantly hindered relevant mechanistic studies. To this end, we have developed new mouse models that recapitulate human metabolic syndrome caused by two commonly prescribed APDs (olanzapine and risperidone). Metabolic analyses revealed that drug-induced hyperphagia is the driving force behind weight gain in both models. Using bulk RNA sequencing, we investigated how APDs altered gene expression in the hypothalamus—a brain region that is critical for appetite control. Our analyses revealed that the melanocortin 4 receptor (Mc4r) was among those that were directly regulated by APD treatment. Furthermore, we found that the obesogenic effect of olanzapine and risperidone depends on Mc4r in Sim1 neurons. Moreover, we found that APDs reduced hypothalamic Mc4r mRNAs before the weight gain. Remarkably, whole-cell electrophysiology experiments demonstrated for the first time that olanzapine and risperidone acutely inhibited Mc4r-expressing neurons in the paraventricular nucleus of the hypothalamus. Furthermore, this inhibition was mediated by a postsynaptic potassium conductance. Collectively, these findings provided the first experimental evidence linking deficits in hypothalamic MC4R signaling to APD-induced metabolic syndrome. In the current project, we propose a multi-discipline approach to investigate the mechanisms underlying 1) how olanzapine and risperidone interact with MC4Rs and perturb their functions; 2) how they inhibit the activity of Mc4r neurons; 3) how both drugs alter the transcriptional and chromatin landscapes in hypothalamic neurons at the single-cell level. These studies have important clinical implications based on the suggestions that MC4R can be a novel therapeutic target for APD-induced weight gain, and that they may guide the development of next-generation antipsychotic medications with fewer metabolic side effects.

项目摘要 抗精神病药物（APD）诱导的代谢综合征是一个紧迫的临床问题，影响数百万人， 患者然而，在实验室动物中模拟其代谢作用的难度显著增加。 阻碍了相关机制的研究。 为此，我们开发了新的小鼠模型，重现了人类代谢综合征引起的 两种常用的APD（奥氮平和利培酮）。代谢分析显示，药物诱导的 在这两种模型中，暴食是体重增加的驱动力。使用批量RNA测序，我们研究了 APD如何改变下丘脑的基因表达，下丘脑是控制食欲的关键大脑区域。我们 分析表明，黑皮质素4受体（Mc 4 r）是APD直接调节的受体之一 治疗此外，我们发现奥氮平和利培酮的致肥胖作用依赖于Mc 4 r。 Sim 1神经元。此外，我们发现APD在体重增加之前降低了下丘脑Mc 4 r mRNA。 值得注意的是，全细胞电生理学实验首次证明奥氮平和 利培酮急性抑制下丘脑室旁核中表达Mc 4 r的神经元。 此外，这种抑制是由突触后钾传导介导的。总的来说，这些发现 提供了第一个实验证据，将下丘脑MC 4 R信号转导缺陷与APD诱导的 代谢综合征 在目前的项目中，我们提出了一个多学科的方法来调查的机制， 1)奥氮平和利培酮如何与MC 4 R相互作用并干扰其功能; 2）它们如何抑制活性 3）两种药物如何改变下丘脑神经元的转录和染色质景观 在单细胞水平上。这些研究具有重要的临床意义的基础上的建议，MC 4 R 可能是APD诱导的体重增加的一个新的治疗靶点，并且它们可能指导 代谢副作用更少的下一代抗精神病药物。