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.

项目摘要抗精神病药（APD）诱导的代谢综合征是一个紧迫的临床问题，影响了数百万患者。但是，在实验动物中建模其代谢作用的难以显着阻碍了相关的机械研究。为此，我们开发了新的鼠标模型，这些模型概括了人类代谢综合征由两个普通规定的APD（奥氮平和利培酮）。代谢分析表明，药物诱导的在这两种模型中，倍率是体重增加的驱动力。使用大量RNA测序，我们研究了 APD如何改变下丘脑中的基因表达，这是对食欲控制至关重要的大脑区域。我们的分析表明，黑色素皮质素4受体（MC4R）是直接受APD调节的人之一治疗。此外，我们发现奥氮平和利培酮的肥胖作用取决于MC4R SIM1神经元。此外，我们发现在体重增加之前，APD会降低下丘脑MC4R mRNA。值得注意的是，全细胞电生理实验首次证明了奥氮平和利培酮急性抑制下丘脑室室核的表达MC4R神经元。此外，这种抑制是由突触后钾电导介导的。总的来说，这些发现提供了第一个实验证据，将下丘脑MC4R信号中的防御措施与APD诱导的代谢综合征。在当前项目中，我们提出了一种多学科方法来研究基本机制 1）奥氮平和利培酮如何与MC4R相互作用并扰动其功能； 2）它们如何抑制活性 MC4R神经元； 3）两种药物如何改变下丘脑神经元中的转录和染色质景观在单细胞级别。这些研究具有MC4R的建议，具有重要的临床意义可以是APD诱导的体重增加的新型热目标，并且可以指导下一代抗精神病药物具有较少的代谢副作用。