Actions of Melanin Concentrating Hormone in the Brain

描述(申请人提供)：肥胖是一种严重的疾病，具有复杂的病因，与多种其他疾病的发展风险增加有关，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，因为罕见的人类肥胖病例是由这些通路中的信号缺陷引起的。我们已经发现一种神经肽，黑色素浓缩激素(MCH)，是能量平衡的重要调节因素，并报道了MCH的遗传消融导致瘦肉型。此外，缺乏MCH(MCH-/-)的小鼠对饮食诱导的肥胖具有抵抗力。同样，其他人报告说，去除啮齿动物的MCH受体，MCHR-1，也会导致消瘦。我们还发现MCH的过度表达与肥胖症的增加有关。我们建立了一个同时缺乏MCH基因和瘦素的模型，即MCH-/-ob/ob，这为MCH调节体重的机制提供了重要的见解。除了对喂养的影响外，妇幼保健品似乎还对能量消耗和运动活动有影响。在这项提案中，我们将完成对MCH-/-ob/ob与ob/ob动物相比的异常的描述。此外，我们将通过评估缺乏MCH的小鼠以及缺乏MCH和瘦素的小鼠的去甲肾上腺素转换来探索我们提出的假设，即MCH通过抑制自主神经活动而起作用。我们将通过检测正常和MCH-/-MCH-/-ob/ob和AMICE的NE转换率，直接检验MCH介导瘦素对交感神经活动的影响的假设。我们还将检验我们已经提出的假设，即MCH作用于调节多巴胺能信号。为此，我们将评估MCH-/-、MCH-/-ob/ob小鼠的DL和D2多巴胺受体、多巴胺转运体和多巴胺水平，并将其与野生型小鼠进行比较。我们将评估通过多巴胺能通路介导的药物的行为反应。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理解人类超重的机制，并对开发预防和治疗肥胖症的治疗方法非常重要。

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.