CNS Pathways Regulating Ghrelin Effects on Body Weight

描述(由申请者提供)：肥胖症发病率的增加是美国面临的一个主要健康问题。幸运的是，在过去的十年里，已经确定了几种关键的荷尔蒙和中枢神经系统(CNS)控制体重和血糖稳态的途径。事实上，我们现在有了一个粗略的中枢神经系统路线图，通过这些路线图，Ghrelin等关键代谢信号发挥其作用，这可能导致有效的战略，以对抗肥胖、糖尿病和饮食失调的发生率。在过去的资助期间，我们试图描绘Ghrelin及其受体生长激素分泌受体(GHSR；Ghrelin Receptor)选择性调节食物摄入量和体重的神经底物。我们创造了一种新型的GHSR缺失小鼠，并发现缺乏Ghrelin信号可以保护小鼠免受饮食诱导的肥胖和糖尿病的影响。在目前的方案中，我们将使用我们的新型小鼠模型来扩展这些观察结果，在该模型中，我们可以选择性地重新激活选定细胞类型中的GHSR表达。我们将确定结状神经节中的迷走感觉神经元是否足以在其他地方缺乏GHSRs的小鼠中恢复Ghrelin的食欲特性。接下来，我们将确定脑干中关键的自主神经调节神经元是否重新表达GHSR，这是正常体重和血糖稳态所必需的。最后，我们还将确定在面对饮食诱导的肥胖时，胰腺中2个细胞中GHSRs的重新激活是否足以恢复Ghrelin抑制胰岛素水平的能力。与公共健康相关：这项研究中提出的实验旨在调查Ghrelin在调节食物摄入量、体重和血糖稳态方面所起的作用。人们希望这些研究将产生新的有针对性的治疗方法，以治疗情绪肥胖、糖尿病和进食障碍，如神经性厌食症和神经性暴食症。

DESCRIPTION (provided by applicant): The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the past decade several key hormones and central nervous system (CNS) pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CNS roadmap through which key metabolic signals like ghrelin exert its effects which may lead to effective strategies to combat the incidence of obesity, diabetes and eating disorders. In the past grant period, we sought to delineate the neural substrates through which ghrelin and its receptor, the growth hormone secretagouge receptor (GHSR; ghrelin receptor) selectively regulate food intake and body weight. We created a novel GHSR null mouse and found that lack of ghrelin signaling protected mice from developing diet-induced obesity and diabetes. In the current proposal, we will extend these observations using our novel mouse model in which we can selectively reactivate GHSR expression in selected cell types. We will identify if vagal sensory neurons in the nodose ganglia are sufficient to restore the orexigenic properties of ghrelin in mice lacking GHSRs everywhere else. We will next determine is GHSR re-expression by key autonomic regulatory neurons in the brainstem is required for normal body weight and glucose homeostasis. Finally, we will also determine if reactivation of GHSRs in 2 cells in the pancreas is sufficient to restore the ability of ghrelin to suppress insulin levels in the face of diet induced obesity. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study have been designed to investigate the role ghrelin plays in regulating food intake, body weight and glucose homeostasis. It is hoped that these studies will result in new targeted therapies to treat mood obesity, diabetes and eating disorders such as anorexia nervosa and bulimia nervosa.