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

瘦素调节的脑干通路控制血糖和能量稳态

基本信息

批准号：
8786551
负责人：
Martin G Myers
金额：
$ 33.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-17 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786551
关键词：
Ablation Acute Adipocytes Affect Animals Area Attenuated Blood Glucose Brain Brain Stem Cell Nucleus Cells Cessation of life Cholecystokinin Designer Drugs Diabetes Mellitus Disease Emergency Situation Emergency response Endocrine Ensure Epidemic Equilibrium Exhibits Failure Fasting Fatty acid glycerol esters Glucagon Health Homeostasis Hunger Hypoglycemia Hypothalamic structure Injury Lateral Leptin Link Malnutrition Mediating Mus Nervous System Physiology Neural Pathways Neurons Neuropeptides Neurophysiology - biologic function Obesity Pain Pathogenesis Pathway interactions Pharmacogenetics Physiological Physiology Play Population Role Site Starvation Stimulus Structure Sympathetic Nervous System System Testing Therapeutic Twin Multiple Birth United States blood glucose regulation design diabetic patient energy balance glycemic control interest leptin receptor midbrain central gray substance novel physiologic stressor prevent programs public health emergency receptor response therapeutic target ventromedial hypothalamic nucleus virus genetics

项目摘要

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.

描述（由申请人提供）：肥胖和糖尿病的流行代表了公共卫生紧急情况。我们必须了解连接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靶点。在这项题为“调节反调节反应的瘦素调节神经通路”的提案中，我们将分析脑干外侧旁臂核 (lPBN) 和导水管周围灰质核 (PAG) 核中表达新型瘦素受体 (LepRb) 的神经通路。这些区域共同包含大部分脑干 LepRb 神经元；每个神经元都包含数量与下丘脑主要核团相似的 LepRb 神经元。 lPBN 和 PAG 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，lPBN 和 PAG LepRb 神经元亚群中 LepRb 的消融增强了对葡萄糖和有害刺激的反调节反应，表明瘦素作用于这些脑干 LepRb 细胞以抑制反调节反应。在此应用中，我们将采用各种依赖于 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以促进整体瘦素作用的机制以及对葡萄糖稳态至关重要的神经功能方面。这些信息反过来将为理解调节血糖控制的机制奠定基础，这对于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治疗目标至关重要。