Actions of Melanin Concentrating Hormone in the Brain

大脑中黑色素浓缩激素的作用

• 批准号: 7037298
• 负责人: ELEFTHERIA MARATOS-FLIER
• 金额: $ 33.6万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037298
• 关键词: autonomic nervous system; behavior test; biological signal transduction; brain; dopamine; dopamine receptor; dopamine transporter; laboratory mouse; leptin; melanins; microdialysis; neuroendocrine system; neuropeptides; neuropharmacology; norepinephrine; obesity; receptor expression; sympathetic nervous system

DESCRIPTION (provided by applicant): Obesity is a serious illness, with a complex etiology, which is associated with increased risk in the development of multiple other morbidities including Type II diabetes, cardiovascular disease, hypertension and some neoplasias. In the United States, rates of obesity have been increasing and at present more than 50% of the population are either overweight or obese. The causes of obesity are poorly understood, however it is clear that molecular signaling pathways in the brain are important as rare cases of human obesity are caused by defective signals in these pathways. We have found that 1 neuropeptide, melanin-concentrating hormone (MCH), is an important regulator of energy balance and have reported that genetic ablation of MCH leads to a lean phenotype. Furthermore, mice lacking MCH (MCH-/-) are resistant to diet induced obesity. Similarly, others reported that ablation of the rodent MCH receptor, MCHR-1, also leads to leanness. We have also found that MCH overexpression is associated with increased adiposity. We generated a model lacking both the MCH gene and leptin, MCH-/- ob/ob, which provided significant insights into the mechanisms by which MCH regulates body weight. In addition to effects on feeding MCH appears to have effects on energy expenditure and locomotor activity. In this proposal we will complete our characterization of the abnormalities of the MCH-/- ob/ob compared to ob/ob animals. Furthermore, we will explore the hypothesis that we developed that MCH acts to suppress autonomic activity by evaluating nor-epinephrine turnover in mice lacking MCH as well as mice lacking both MCH and leptin. We will directly test the hypothesis that MCH mediates effects of leptin on sympathetic activity by examining NE turnover in normal and MCH-/- MCH-/- ob/ob and amice. We will also examine the hypothesis that we have developed that MCH acts to regulate dopaminergic signaling. To do this, we will assess Dl and D2 dopamine receptors, dopamine transporters and dopamine levels in MCH-/-, MCH -/- ob/ob mice and compare these to wild type mice. We will evaluate behavioral responses to pharmacologic agents mediated through dopaminergic pathways. We will also perform microdialysis experiments to evaluate dopamine activity in freely moving mice in real time. Understanding these pathways will help understand mechanisms by which humans gain excess weight and are important in developing treatments for the prevention and treatment of obesity.

描述（由申请方提供）：肥胖是一种严重疾病，具有复杂的病因学，与多种其他疾病（包括II型糖尿病、心血管疾病、高血压和某些肿瘤）的发生风险增加相关。在美国，肥胖率一直在增加，目前超过50%的人口超重或肥胖。肥胖的原因知之甚少，但很明显，大脑中的分子信号传导通路是重要的，因为人类肥胖的罕见病例是由这些通路中的缺陷信号引起的。我们已经发现，1神经肽，黑色素浓集激素（MCH），是一个重要的调节能量平衡，并报告说，基因消融MCH导致精益表型。此外，缺乏MCH（MCH-/-）的小鼠对饮食诱导的肥胖具有抗性。类似地，其他人报告说，啮齿动物MCH受体MCH-I的消融也导致消瘦。我们还发现MCH过表达与肥胖增加有关。我们产生了一个模型，缺乏MCH基因和瘦素，MCH-/- ob/ob，这提供了显着的见解MCH调节体重的机制。除了对喂养的影响外，MCH似乎对能量消耗和自发活动也有影响。在本提案中，我们将完成MCH-/- ob/ob与ob/ob动物相比的异常表征。此外，我们将探讨的假设，我们开发的MCH行为，以抑制自主活动，通过评估去甲肾上腺素周转缺乏MCH以及小鼠缺乏MCH和瘦素。我们将通过检查正常和MCH-/- MCH-/- ob/ob和amice中的NE周转来直接检验MCH介导瘦素对交感神经活性的影响的假设。我们还将研究我们已经开发的MCH作用于调节多巴胺能信号传导的假设。为此，我们将评估MCH-/-、MCH -/- ob/ob小鼠中的D1和D2多巴胺受体、多巴胺转运蛋白和多巴胺水平，并将其与野生型小鼠进行比较。我们将评估通过多巴胺能途径介导的药理学药物的行为反应。我们还将进行微透析实验，以评估真实的时间内自由活动小鼠的多巴胺活性。了解这些途径将有助于了解人类体重增加的机制，并在开发预防和治疗肥胖的治疗方法方面具有重要意义。