Actions of Melanin Concentrating Hormone in the Brain

描述（由申请人提供）：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。肥胖的原因尚不清楚，但很明显，大脑中的分子信号通路很重要，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。我们发现1神经肽，即黑色素浓缩激素（MCH），是能量平衡的重要调节因子，并报道了MCH的基因消融导致瘦表型。此外，缺乏MCH （MCH-/-）的小鼠对饮食引起的肥胖有抵抗力。类似地，其他研究报道，啮齿动物MCH受体mhr -1的消融也会导致肥胖。我们还发现，MCH过表达与肥胖增加有关。我们建立了一个缺少MCH基因和瘦素的模型，MCH-/- ob/ob，这为MCH调节体重的机制提供了重要的见解。除了对摄食的影响外，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MCH-/- ob/ob与ob/ob动物的异常特征。此外，我们将通过评估缺乏MCH的小鼠以及同时缺乏MCH和瘦素的小鼠的去肾上腺素转换，探索我们提出的MCH抑制自主神经活动的假设。我们将通过检测正常、MCH-/- MCH-/- ob/ob和小鼠的NE转换，直接验证MCH介导瘦素对交感神经活动影响的假设。我们还将检验我们提出的假说，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途径介导的药物对行为的反应。我们还将进行微透析实验，以实时评估自由运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，对开发预防和治疗肥胖的治疗方法也很重要。

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 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.