A Leptin-Regulated Brainstem Pathway That Controls Glucose and Energy Homeostasis

摘要 肥胖症和糖尿病的流行是一种公共卫生紧急情况。我们必须了解 联系能量平衡和葡萄糖稳态的机制，因为这些可能代表潜在的治疗 目标的在这项题为“一种瘦素调节的神经通路， 我们将分析新的瘦素受体（LepRb）表达神经通路在脑干外侧 臂旁核（IPBN）和导水管周围灰质（PAG）。这些地区共同包含了大多数 脑干LepRb神经元;每个包含LepRb神经元的数量类似于那些发现在主要 下丘脑核来自lPBN和PAG LepRb细胞的投射（沿着它们的激活， 生理应激源，如低血糖和不适）表明这些神经元在 调节反调节反应。事实上，在IPBN和PAG的亚群中LepRb的消融 LepRb神经元增强了对葡萄糖依赖性和伤害性刺激的反调节反应，这表明， 瘦素作用于这些脑干LepRb细胞以抑制反调节反应。在本申请中，我们 将采用各种依赖cre的病毒和遗传系统来了解cre的功能，重要性， 这些脑干LepRb神经元的作用机制。 这些研究揭示了瘦素在脑干中作用的机制，从而有助于瘦素的整体作用 以及对葡萄糖稳态至关重要的神经功能方面。这些信息将反过来奠定 了解调节血糖控制的机制的基础，这对于我们寻求 确定肥胖和糖尿病这对孪生流行病的发病机制和潜在的治疗靶点。

Abstract The epidemics of obesity and diabetes represent a public health emergency. We must understand the mechanisms that link energy balance and glucose homeostasis, as these may represent potential therapeutic targets. In this proposal, entitled, "A leptin-regulated neural pathway that modulates the counter-regulatory response," we will analyze novel leptin receptor (LepRb)-expressing neural pathways in the brainstem lateral parabrachial (lPBN) and periaqueductal grey (PAG) nuclei. Together, these regions contain the majority of brainstem LepRb neurons; each contains numbers of LepRb neurons similar to those found in major hypothalamic nuclei. The projections from lPBN and PAG LepRb cells (along with their activation by physiologic stressors such as hypoglycemia and discomfort) suggest the importance of these neurons in modulating the counter-regulatory response. Indeed, ablation of LepRb in a subpopulation of lPBN and PAG LepRb neurons enhances the counter-regulatory response to glucoprivic and noxious stimuli, suggesting that leptin acts on these brainstem LepRb cells to restrain the counter-regulatory response. In this application, we will employ a variety of cre-dependent viral and genetic systems to understand the function, importance, and mechanisms of action of these brainstem LepRb neurons. These studies reveal the mechanisms by which leptin acts in the brainstem to contribute to overall leptin action and aspects of neural function that are crucial for glucose homeostasis. This information will in turn lay the groundwork for understanding mechanisms that modulate glycemic control, which is crucial as we seek to determine the pathogenesis of, and potential therapeutic targets for the twin epidemics of obesity and diabetes.