Leptin Action and Central Melanocortin Systems

肥胖症发病率的增加是美国面临的主要健康问题。此外，机制 神经性厌食症的潜在原因仍然知之甚少。幸运的是，在过去的十年里， 已经鉴定了控制体重和葡萄糖稳态的激素和CMS途径。 事实上，我们现在有一个粗略的中枢神经系统路线图，通过它，瘦素等关键代谢信号发挥作用 这可能会导致有效的战略，以打击肥胖和饮食失调的发病率。过去 在此期间，我们试图描述黑皮质素4受体（MC4-Rs） 选择性地调节食物摄入、体重和葡萄糖稳态。我们关注的是 瘦素调节的神经元系统和MC4-R系统的相互作用。总的来说，我们的数据表明， 脑中的不同部位介导MC4-R激动剂调节体重，食物摄入， 和葡萄糖稳态。具体地说，我们发现室旁核的神经元， 下丘脑调节食物摄入，但不调节能量消耗。在目前的提案中，我们将 使用我们的小鼠模型扩展这些观察结果，在该模型中我们可以选择性地重新激活MC4-R表达。 我们将确定苍白中缝核的神经元是否足以调节能量消耗。我们还将 确定自主神经节前神经元中MC4-Rs的再激活是否足以挽救减少的 能量消耗和糖尿病特征的MC4-R缺乏。最后，我们将确定是MC4-R 正常体重和葡萄糖稳态需要自主节前神经元的表达 通过选择性删除表达MC4-Rs的小鼠自主节前神经元中的MC4-Rs， 在大脑的其他地方。

The increasing incidence of obesity is a major health issue facing the USA. Moreover, the mechanisms underlying anorexia nervosa remain poorly understood. Fortunately, in the past decade several key hormones and CMS pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like leptin exert its effects which may lead to effective strategies to combat the incidence of obesity and eating disorders. In the past grant period, we sought to delineate the neural substrates through which melanocortin 4 receptors (MC4-Rs) selectively regulate food intake, body weight and glucose homeostasis. We focused on the potential interactions of leptin-regulated neuronal systems and MC4-R systems. Collectively, our data suggests that different sites in the brain mediate different effects of MC4-R agonists to regulate body weight, food intake, and glucose homeostasis. Specifically, we found that neurons in the paraventricular nucleus of the hypothalamus regulate food intake, but do not regulate energy expenditure. In the current proposal, we will extend these observations using our mouse model in which we can selectively reactivate MC4-R expression. We will identify if neurons in the raphe pallidus are sufficient to regulate energy expenditure. We will also determine if reactivation of MC4-Rs in autonomic preganglionic neurons is sufficient to rescue the reduced energy expenditure and diabetes characteristic of MC4-R deficiency. Finally, we will determine is MC4-R expression by autonomic preganglionic neurons is required for normal body weight and glucose homeostasis by selectively deleting MC4-Rs in autonomic preganglionic neurons in mice that express MC4-Rs everywhere else in the brain.