Hypothalamic Serotonin Receptors and Olanzapine-induced Metabolic Syndrome

下丘脑血清素受体和奥氮平诱导的代谢综合征

基本信息

批准号：
9363340
负责人：
Chen Liu
金额：
$ 40.5万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363340
关键词：
ART protein Adult Affect Agonist Antipsychotic Agents Autistic Disorder Bipolar Disorder Body Weight Brain C57BL/6 Mouse Candidate Disease Gene Chronic Clinical Clozapine Data Diabetes Mellitus Diet Dyslipidemias Eating Energy Metabolism Equilibrium Etiology Female General Population Generations Genetic Glucose Glucose tolerance test Goals Human Hyperphagia Hypothalamic structure Impairment Individual Insulin Knockout Mice Link Major Depressive Disorder Mediating Metabolic Metabolic syndrome Midbrain structure Modeling Mus Neural Pathways Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Pathway interactions Patients Pharmaceutical Preparations Physical activity Plasma Population Pro-Opiomelanocortin Resources Risk Role Schizophrenia Series Serotonergic System Serotonin Serotonin Agonists Serotonin Receptor 5-HT1B Serotonin Receptor 5-HT2C Site Solid Symptoms Testing Therapeutic Time Transgenic Mice Weight Weight Gain combat dopamine system energy balance evidence base experimental study gender difference genome wide association study glucose metabolism in vivo monoamine mouse model multidisciplinary neural circuit neuromechanism neuropsychiatry olanzapine pre-clinical receptor response serotonin receptor success therapeutic evaluation tool

项目摘要

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.

项目概要奥氮平和氯氮平等第二代抗精神病药 (SGA) 是基本药物此外，对于全世界数百万精神分裂症患者来说，过去十年是指数级的。增加其对其他神经精神疾病的使用，包括双相情感障碍、重度抑郁症尽管其疗效广泛且锥体外系症状的风险较低，但大多数 SGA 具有以下特点：与严重的药物引起的代谢综合征有关，其特征是体重过度增加， SGA 治疗后不久就会出现血脂异常、2 型糖尿病和肥胖。女性受试者患代谢综合征的风险明显更高，而且发病速度快。性别差异强烈表明 SGA 诱发的代谢综合征存在不同的病因。不幸的是，尽管人们花费了大量的资源和努力来对抗肥胖和糖尿病对于一般人群，在理解或治疗药物引起的代谢方面几乎没有取得进展干扰。对人类患者进行的全基因组关联研究表明大脑血清素 (5-HT) 的作用然而，之前人们一直在努力辨别它们的作用。由于使用改良的奥氮平在小鼠中复制 SGA 诱导的代谢综合征的困难而受到阻碍。节食后，我们能够可靠地在 C57BL/6 小鼠中重现体重过度增加和糖尿病的成功。在小鼠中模拟奥氮平诱导的代谢综合征为我们提供了精确表征的机会此外，它使我们能够应用复杂的小鼠。揭示介导奥氮平代谢作用的候选基因和途径的遗传工具。我们将对转基因小鼠进行一系列体内分析，以探究个体的贡献我们发现奥氮平通过血清素受体发挥作用。不同下丘脑神经元群体中的血清素 2c 受体 (Htr2c) 和血清素 1b 受体 (Htr1b) 损害能量和葡萄糖代谢这一假设是有证据支持的，包括令人兴奋的、可靠的。此处首次提供的初步数据表明奥氮平对食物的影响缺乏 Htr2c 或 Htr1b 的小鼠的摄入量和体重增加受到抑制实验将包括针对 Htr2c。特别是在下丘脑 POMC 神经元和下丘脑 AgRP 神经元中的 Htr1b 中，以确定是否 Htr2c 和 Htr1b 作用于这些位点以介导奥氮平的不良代谢作用我们还将测试。 Htr2c 特异性激动剂对奥氮平喂养小鼠的治疗潜力因此，得出了阳性结果。这些研究将为特异性5-HT受体的临床应用提供必要的证据和理论依据激动剂治疗数百万患者由 SGA 引起的代谢综合征。