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

描述(申请人提供)：肥胖症和糖尿病的流行代表公共卫生紧急情况。我们必须了解能量平衡和葡萄糖稳态之间的联系机制，因为这些可能是潜在的治疗靶点。在这项题为“调节反调节反应的瘦素调节的神经通路”的提案中，我们将分析脑干外侧臂旁核(LPBN)和中脑导水管周围灰质(PAG)核中表达新的瘦素受体(LepRb)的神经通路。这些区域包含脑干LepRb神经元的大部分；每个区域包含的LepRb神经元数量与主要下丘脑核团中的LepRb神经元数量相似。来自lPBN和PAG的LepRb细胞的投射(以及它们被低血糖和不适等生理应激源激活)表明这些神经元在调节反调节反应中的重要性。事实上，在lPBN和PAG中的LepRb神经元亚群中消融LepRb可以增强对葡聚糖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细胞来抑制反调节反应。在这个应用中，我们将使用各种依赖cre的病毒和遗传系统来了解这些脑干LepRb神经元的功能、重要性和作用机制。这些研究揭示了瘦素在脑干中作用的机制，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。这些信息将反过来为理解调节血糖控制的机制奠定基础，这在我们寻求确定肥胖和糖尿病这两种流行病的发病机制和潜在的治疗目标时至关重要。

DESCRIPTION (provided by applicant): 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.