Leptin Action and Central Melanocortin Systems

不断增加的肥胖率是美国面临的一个主要健康问题。此外，这些机制 潜在的神经性厌食症仍然知之甚少。幸运的是，在过去的十年里，有几个关键 激素和CMS途径控制体重和葡萄糖动态平衡已被确定。 事实上，我们现在有了一个粗略的中枢神经系统路线图，瘦素等关键代谢信号通过这些路线图发挥作用 这可能会导致有效的战略，以对抗肥胖和饮食失调的发生率。在过去 在授权期，我们试图描绘黑素皮质素4受体(MC4-Rs)通过的神经底物。 选择性地调节食物摄入量、体重和血糖动态平衡。我们关注的是潜在的 瘦素调节的神经系统和MC4-R系统的相互作用。总而言之，我们的数据表明 大脑中不同的部位调节MC4-R激动剂调节体重，食物摄入量， 和葡萄糖动态平衡。具体地说，我们发现脑室旁核中的神经元 下丘脑调节食物摄入量，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的表达。 我们将确定中缝苍白核中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受体的重新激活是否足以挽救减少的 MC4-R缺乏症的能量消耗和糖尿病特征。最后，我们将确定MC4-R 自主神经节前神经元的表达是正常体重和血糖稳态所必需的 通过选择性删除表达MC4-Rs的小鼠自主神经节前神经元中的MC4-Rs 大脑中的其他地方。

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.