Hypothalamic MC4Rs and Antipsychotic Drug-Induced Metabolic Syndrome

项目总结 抗精神病药物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 病人。然而，在实验室动物身上模拟它们的代谢影响的难度很大。 阻碍了相关的机制研究。 为此，我们开发了新的小鼠模型，它概括了人类代谢综合征引起的 两种常用的APDS(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，吞噬过多都是体重增加的驱动力。使用批量RNA测序，我们研究了 APDS如何改变下丘脑的基因表达--这是一个对食欲控制至关重要的大脑区域。我们的 分析表明，黑素皮质素4受体(Mc4r)是受apd直接调节的受体之一。 治疗。此外，我们还发现奥氮平和利培酮的致肥胖作用依赖于Mc4r。 Sim1神经元。此外，我们发现APDS在体重增加之前降低了下丘脑Mc4rmRNAs的表达。 值得注意的是，全细胞电生理实验首次证明奥氮平和 利培酮可显著抑制下丘脑室旁核Mc4r阳性神经元的表达。 此外，这种抑制是由突触后钾电导介导的。总而言之，这些发现 提供了第一个实验证据，将下丘脑MC4R信号缺陷与动作电位反应诱导 代谢综合征。 在目前的项目中，我们提出了一种多学科的方法来研究潜在的机制 1)奥氮平和利培酮如何与MC4Rs相互作用并干扰其功能；2)它们如何抑制MC4Rs的活性 Mc4r神经元；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。基于MC4R的建议，这些研究具有重要的临床意义 可以作为一种新的治疗靶点来治疗apd诱导的体重增加，并可能指导 代谢副作用较少的下一代抗精神病药物。

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.