Hypothalamic Serotonin Receptors and Olanzapine-induced Metabolic Syndrome

项目总结 第二代抗精神病药物(SGA)，如奥氮平和氯氮平是基本药物 全球数以百万计的精神分裂症患者。此外，过去十年见证了指数级的增长 增加对其他神经精神疾病的使用，包括双相情感障碍、严重抑郁 精神障碍和自闭症。尽管它们的疗效广泛，锥体外系症状的风险很低，但大多数SGA 与大量药物诱导的代谢综合征有关，这种综合征的特征是体重过度增加， 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， 在女性受试者中，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SGA诱导的代谢综合征有不同的病因。 不幸的是，尽管在与肥胖和糖尿病作斗争上花费了大量的资源和努力， 在普通人群中，在理解或治疗药物诱导的代谢方面进展甚微 骚乱。 对人类患者的全基因组关联研究表明，脑内5-羟色胺(5-HT)起着一定的作用 SGA诱导的代谢综合征中的受体。然而，之前辨别他们角色的努力一直是 受阻于难以复制SGA诱导的小鼠代谢综合征。使用改良的奥氮平 通过饮食，我们能够可靠地复制C57BL/6小鼠的过度体重增加和糖尿病。在中国取得的成功 奥氮平诱导的小鼠代谢综合征模型为我们提供了一个精确描述 奥氮平治疗小鼠的代谢变化。此外，它还允许我们应用复杂的鼠标 基因工具，以解开奥氮平代谢影响的候选基因和途径。这里, 我们将在转基因小鼠身上进行一系列体内分析，以询问个体的贡献 奥氮平诱导的代谢综合征的5-羟色胺受体。我们假设奥氮平通过 下丘脑神经元中5-羟色胺2c受体(Htr2c)和5-羟色胺1b受体(Htr1b) 损害能量和葡萄糖代谢。这一假设是以证据为基础的，包括令人兴奋的、可靠的 我们第一次展示了奥氮平对食物的影响的初步数据 缺乏Htr2c或Htr1b的小鼠摄入和体重增加变得迟钝。实验将包括瞄准Htr2c 特别是在下丘脑POMC神经元和Htr1b在下丘脑AgRP神经元中确定 Htr2c和Htr1b作用于这些部位，调节奥氮平的不良代谢效应。我们还将测试 Htr2c特异性激动剂对喂饲奥氮平小鼠的治疗潜力。因此，积极的结果来自 这些研究将为特异性5-羟色胺受体的临床应用提供必要的证据和理论基础。 用于治疗SGA诱导的代谢综合征的激动剂在数百万患者中。

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.