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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要抗精神病药物（APD）引起的代谢综合征是一个紧迫的临床问题，影响着数百万人然而，在实验动物中模拟其代谢影响的难度很大。阻碍了相关机理研究。为此，我们开发了新的小鼠综合症模型，该模型概括了人类代谢引起的两种常用的 APD（奥氮平和利培酮）代谢分析显示，这是药物引起的。我们利用批量 RNA 测序进行了研究，认为食欲亢进是这两种模型中体重增加的驱动力。 APD 如何改变下丘脑（对于食欲控制至关重要的大脑区域）的基因表达。分析显示黑皮质素 4 受体 (Mc4r) 是 APD 直接调节的受体之一此外，我们发现奥氮平和利培酮的致肥作用取决于 Mc4r。此外，我们发现 APD 在体重增加之前减少了下丘脑 Mc4r 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 Mc4r 的神经元。此外，这种抑制是由突触后钾电导介导的。提供了第一个将下丘脑 MC4R 信号传导缺陷与 APD 诱导相关的实验证据代谢综合征。在当前的项目中，我们提出了一种多学科方法来研究潜在的机制 1) 奥氮平和利培酮如何与 MC4R 相互作用并干扰其功能 2) 它们如何抑制活性； Mc4r 神经元的作用；3) 两种药物如何改变下丘脑神经元的转录和染色质景观基于 MC4R 的建议，这些研究在单细胞水平上具有重要的临床意义。可以成为 APD 引起的体重增加的新治疗靶点，并且它们可以指导具有较少代谢副作用的下一代抗精神病药物。