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

• 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
• 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

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.

项目摘要 第二代抗精神病药（SGA），例如奥氮平和氯氮平是必不可少的药物 全球数百万个精神分裂症患者。此外，过去十年见证了指数 增加其对其他神经精神病疾病的用途，包括躁郁症，重度抑郁症 障碍和自闭症。尽管它们的效率很高，并且大多数SGA都有腹膜外症状的风险低 与大量药物诱导的代谢综合征有关，其特征是体重增加过多， 血脂异常和2型糖尿病。 SGA治疗后不久，肥胖和糖尿病经常发育。而且， 女性受试者中代谢综合征的风险明显更高。快速疾病发作以及 性别差异强烈表明了SGA诱导的代谢综合征的不同病因。 不幸的是，尽管已经花费了巨大的资源和努力来与肥胖和糖尿病作斗争 一般人群，在理解或治疗药物诱导的代谢方面取得了很少的进展 干扰。 人类患者全基因组的关联研究已对脑血清素发挥作用（5-HT） SGA诱导的代谢综合征的接收者。但是，以前识别其角色的努力已经 由于难以复制小鼠中SGA诱导的代谢综合征的阻碍。使用改良的奥氮平 饮食，我们能够可靠地重现C57BL/6小鼠的体重增加和糖尿病。成功 在小鼠中对奥氮平诱导的代谢综合征进行建模为我们提供了精确特征的机会 奥氮平治疗的小鼠的代谢改变。此外，它使我们能够应用复杂的鼠标 阐明介导奥氮平的代谢作用的候选基因和途径的遗传工具。这里， 我们将在转基因小鼠中进行一系列体内分析，以询问个体的贡献 5-羟色胺受体到奥氮平诱导的代谢综合征。我们假设奥氮平通过 在下丘脑神经元不同种群中 损害能量和葡萄糖代谢。该假设是基于证据的，包括令人兴奋的扎实 首次提供的初步数据我们表明奥氮平对食物的影响 缺乏HTR2C或HTR1B的小鼠，摄入量和体重增加钝化。实验将包括针对HTR2C 特别是下丘脑POMC神经元和下丘脑AGRP神经元中的HTR1B HTR2C和HTR1B在这些位点作用，以介导奥氮平的不良代谢作用。我们还将测试 奥氮平喂养小鼠中HTR2C的特异性激动剂的治疗潜力。因此，来自 这些研究将为特定5-HT接收器的临床使用提供必要的证据和理由 激动剂治疗数百万患者的SGA诱导的代谢综合征。