Hypothalamic Serotonin Receptors and Olanzapine-induced Metabolic Syndrome

项目摘要 第二代抗精神病药（SGA），如奥氮平和氯氮平是基本药物 为全世界数百万精神分裂症患者提供治疗。此外，在过去十年中， 它们在其他神经精神疾病中的用途增加，包括双相情感障碍、重度抑郁症， 和自闭症。尽管它们的疗效广泛，锥体外系症状的风险低，但大多数SGAs已经被 与以体重过度增加为特征的大量药物诱导的代谢综合征有关， 血脂异常和2型糖尿病。肥胖和糖尿病通常在SGA治疗后不久发生。此外，委员会认为， 女性受试者患代谢综合征的风险明显更高。疾病的快速发作以及 性别差异强烈提示了一种独特的潜在的SGA诱导的代谢综合征的病因学。 不幸的是，尽管已经花费了巨大的资源和努力来对抗肥胖和糖尿病， 一般人群中，在了解或治疗药物诱导的代谢方面几乎没有进展 干扰. 在人类患者中进行的全基因组关联研究表明，脑5-羟色胺（5-HT） 受体在SGA诱导的代谢综合征中的作用。然而，以前的努力，以辨别他们的作用一直是 由于难以在小鼠中复制SGA诱导的代谢综合征而受阻。使用改良的奥氮平 饮食，我们能够可靠地再现C57 BL/6小鼠的过度体重增加和糖尿病。的成功 在小鼠中建立奥氮平诱导的代谢综合征模型为我们提供了一个精确表征 奥氮平处理小鼠的代谢改变。此外，它使我们能够应用复杂的小鼠遗传学， 工具，以解开候选基因和途径，介导奥氮平的代谢作用。在这里，我们将 在转基因小鼠中进行一系列体内分析，以询问个体血清素的贡献。 奥氮平诱导的代谢综合征的受体。我们假设奥氮平通过血清素起作用 2c受体（Htr 2c）和5-羟色胺1b受体（Htr 1b）在不同群体的下丘脑神经元损害 能量和葡萄糖代谢。这一假设是有证据的，包括令人兴奋的，坚实的初步数据 这是我们第一次展示奥氮平对食物摄入和体重增加的影响， 在缺乏Htr 2c或Htr 1b的小鼠中是钝化的。实验将包括在下丘脑中特异性靶向Htr 2c POMC神经元和下丘脑AgRP神经元中的Htr 1b，以确定Htr 2c和Htr 1b是否作用于这些神经元。 介导奥氮平不良代谢作用的位点。我们还将测试 奥氮平喂养小鼠中Htr 2c特异性激动剂。因此，这些研究的积极结果将提供 临床使用特异性5-HT受体激动剂治疗SGA诱导的 代谢综合征的患者。

PROJECT SUMMARY Second-generation antipsychotics (SGAs) such as olanzapine and clozapine are essential medications for millions of schizophrenia patients worldwide. Moreover, the last decade has witnessed an exponential increase of their uses for other neuropsychiatric conditions including bipolar disorder, major depressive disorder, and autism. Despite their broad efficacy and low risks for extrapyramidal symptoms, most SGAs have been linked to substantial drug-induced metabolic syndrome that is characterized by excessive weight gain, dyslipidemia, and type-2 diabetes. Obesity and diabetes often develop shortly after SGA treatment. Moreover, the risk for metabolic syndrome is significantly higher in female subjects. The rapid disease onset as well as the gender difference strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome. Unfortunately, while tremendous resources and efforts have been spent combating obesity and diabetes in the general population, little progress has been made toward understanding or treating drug-induced metabolic disturbances. Genome-wide association studies in human patients have implicated a role for brain serotonin (5-HT) receptors in SGA-induced metabolic syndrome. However, previous efforts to discern their roles have been hindered by the difficulty to replicate SGA-induced metabolic syndrome in mice. Using a modified olanzapine diet, we are able to reliably reproduce excessive weight gain and diabetes in C57BL/6 mice. The success in modeling olanzapine-induced metabolic syndrome in mice provides us an opportunity to precisely characterize metabolic alterations in olanzapine-treated mice. Furthermore, it allows us to apply sophisticated mouse genetic tools to unraveling candidate genes and pathways that mediate olanzapine’s metabolic effects. Here, we will carry out a series of in vivo analyses in transgenic mice to interrogate the contribution of individual serotonin receptors to olanzapine-induced metabolic syndrome. We hypothesize that olanzapine acts through serotonin 2c receptor (Htr2c) and serotonin 1b receptor (Htr1b) in distinct populations of hypothalamic neurons to impair energy and glucose metabolism. This hypothesis is evidence-based, including exciting, solid preliminary data that is presented here for the first time in which we show that olanzapine’s effect on food intake and weight gain is blunted in mice lacking Htr2c or Htr1b. Experiments will include targeting Htr2c specifically in hypothalamic POMC neurons and Htr1b in hypothalamic AgRP neurons to determine whether Htr2c and Htr1b act on these sites to mediate the untoward metabolic effects of olanzapine. We will also test the therapeutic potential of specific agonist for Htr2c in olanzapine-fed mice. Therefore, positive results from these studies will provide necessary evidence and rationale for the clinical use of specific 5-HT receptor agonists to treat SGA-induced metabolic syndrome in millions of patients.