Role of Vagal Afferents in Maintainence of Body Weight and Glucose Homeostasis

描述(由申请人提供)：代谢失调疾病是发展中国家的主要公共卫生问题。肥胖与多种健康问题有关，并被认为是一种日益严重的流行病，而II型糖尿病的发病率继续上升。肠道-脑轴的许多紊乱，或中枢神经通路对消化系统信息的反应，都与肥胖和II型糖尿病有关。然而，对于来自外围的信息到达这些中心内环境平衡部位的途径，人们知之甚少。一些证据表明，传入迷走神经可能在能量平衡的神经调节中发挥关键作用。发现这些途径可能会为能量平衡障碍的治疗带来新的靶点。这里提出的研究试图在小鼠身上使用允许特定消融迷走神经感觉神经元的遗传和药物操作的组合，确定在食物喂养和饮食诱导的肥胖下，是否需要迷走神经传入来维持长期的体重和血糖稳态，是否需要迷走神经传入来发挥噻唑烷二酮类药物的抗糖尿病作用，以及迷走神经传入是否对于CB1R拮抗剂的抗糖尿病作用是必需的。 公共卫生相关性：肥胖症和糖尿病目前在美国很流行，如果不加以控制，这些疾病的增长速度将导致发病率和死亡率的大幅增加，以及随之而来的医疗费用。然而，几乎没有有效的药物治疗肥胖症。通过研究迷走感觉神经元在维持体重和血糖稳态中的作用，这里提出的研究可能会为代谢失调疾病的治疗带来新的靶点。

DESCRIPTION (provided by applicant): Diseases of metabolic dysregulation are major public health concerns in the developing world. Obesity is associated with multiple health problems and is being recognized as a growing epidemic, while incidence of Type II diabetes continues to rise. Many derangements in the gut-to-brain axis, or the response of central neural pathways to information from the digestive system, have been implicated in obesity and Type II diabetes. However, relatively little is known about the pathways by which information from the periphery reaches these central homeostatic sites. Several lines of evidence suggest that the afferent vagal nerve may play a key role in neural regulation of energy homeostasis. Uncovering these pathways may result in new targets for treatment of energy balance dysfunction. The studies proposed here seek to, using a combination of genetic and pharmacologic manipulations in mice which allow for specific ablation of vagal sensory neurons, determine whether vagal afferents are required for the maintenance of long-term body weight and glucose homeostasis under chow feeding and in diet-induced obesity, if vagal afferents are required for the anti-diabetic actions of thiazolidinediones, and if vagal afferents are necessary for the anti-diabetic action of the CB1R antagonist class of drugs. PUBLIC HEALTH RELEVANCE: Relevance Obesity and diabetes are now epidemic in the United States, and if left unchecked, the growing rate of these diseases will cause a tremendous increase in morbidity and mortality, as well as ensuing health care costs. However, few effective pharmacological therapies for obesity exist. By examining the role of vagal sensory neurons in maintenance of body weight and glucose homeostasis, the studies proposed here could result in a new target for treatment of diseases of metabolic dysregulation.