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Actions of Melanin Concentrating Hormone in the Brain

大脑中黑色素浓缩激素的作用

基本信息

批准号：
7997922
负责人：
ELEFTHERIA MARATOS-FLIER
金额：
$ 8.07万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-21 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7997922
关键词：
Ablation Acute Agonist Amphetamines Animals Area Attenuated Basal metabolic rate Behavioral Body Weight Body Weight decreased Brain Brown Fat Cardiovascular Diseases Cells Chronic Circadian Rhythms Complex Control Animal Corpus striatum structure Data Development Diet Dopamine Dopamine Antagonists Dopamine D2 Receptor Energy Metabolism Epinephrine Etiology Exhibits Expenditure Fatty acid glycerol esters Food Genes Genetic Glucocorticoids Grant Homeostasis Human Hyperphagia Hypertension Hypothalamic structure Infusion procedures Ingestion Insulin Intake Knockout Mice Label Lateral Lead Leptin Leptin deficiency Link Mediating Metabolic Microdialysis Mild obesity Modeling Molecular Morbid Obesity Morbidity - disease rate Motor Activity Mus Neoplasms Neuraxis Neurons Neuropeptides Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Obesity Output Overweight Pathway interactions Peptides Peripheral Phenotype Physiological Play Population Prevention Principal Investigator Process Proteins Pump Rattus Regulation Reporting Research Personnel Resistance Rest Risk Rodent Role Secondary to Signal Pathway Signal Transduction Substantia nigra structure Suggestion Sympathetic Nervous System Techniques Testing Thinness Time United States Ventral Tegmental Area Weight Wild Type Mouse attenuation dopamine transporter energy balance feeding ghrelin glucose tolerance hindbrain hypocretin improved insight locomotor deficit melanin-concentrating hormone melanin-concentrating hormone receptor mouse model obesity treatment overexpression programs putamen receptor research study response restoration

项目摘要

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 one 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（由申请人提供）：肥胖是一种严重疾病，病因复杂，与多种其他疾病的风险增加相关，包括 II 型糖尿病、心血管疾病、高血压和一些肿瘤。在美国，肥胖率一直在上升，目前超过50%的人口超重或肥胖。人们对肥胖的原因知之甚少，但很明显，大脑中的分子信号通路很重要，因为极少数人类肥胖病例是由这些通路中的信号缺陷引起的。我们发现一种神经肽——黑色素浓缩激素（MCH），是能量平衡的重要调节剂，并报告说，MCH 的基因消除会导致瘦表型。此外，缺乏 MCH (MCH-/-) 的小鼠对饮食引起的肥胖具有抵抗力。同样，其他人报告说，啮齿动物 MCH 受体 MCHR-1 的消融也会导致瘦身。我们还发现 MCH 过度表达与肥胖增加有关。我们生成了一个缺乏 MCH 基因和瘦素的模型 MCH-/- ob/ob，它为 MCH 调节体重的机制提供了重要的见解。除了对进食的影响之外，MCH 似乎对能量消耗和运动活动也有影响。在本提案中，我们将完成对 MCH-/- ob/ob 与 ob/ob 动物相比异常的表征。此外，我们将通过评估缺乏 MCH 以及同时缺乏 MCH 和瘦素的小鼠的去甲肾上腺素周转情况来探索我们提出的 MCH 抑制自主活动的假设。我们将通过检查正常和 MCH-/- MCH-/- ob/ob 和小鼠中的 NE 转换来直接检验 MCH 介导瘦素对交感神经活动的影响的假设。我们还将检验我们提出的 MCH 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，并将它们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对药物的行为反应。我们还将进行微透析实验，实时评估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，并且对于开发预防和治疗肥胖的疗法非常重要。