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

• 批准号: 8652155
• 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
• 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/8652155
• 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; Endocrine; Ensure; Epidemic; Equilibrium; Exhibits; Failure; Fasting; Fatty acid glycerol esters; Glucagon; 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; public health relevance; receptor; response; therapeutic target; ventromedial hypothalamic nucleus; virus genetics

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.

摘要 肥胖和糖尿病的流行代表着一种公共卫生紧急状态。我们必须了解 将能量平衡和葡萄糖稳态联系起来的机制，因为这些可能是潜在的治疗方法 目标。在这份题为《瘦素调节的神经通路调节反调节的神经通路》的提案中 我们将分析脑干外侧区表达瘦素受体(LepRb)的新神经通路 臂旁核(LPBN)和导水管周围灰质(PAG)核。这些区域总共包含了大部分 脑干LepRb神经元；每个神经元包含的LepRb神经元数量与主要 下丘脑核团。LPBN和PAG LepRb细胞的投射(以及它们的激活 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lPBN和PAG的一个亚群中消融LepRb LepRb神经元增强了对葡聚糖和伤害性刺激的反调节反应，表明 瘦素作用于这些脑干LepRb细胞以抑制逆调节反应。在此应用程序中，我们 将利用各种依赖于cre的病毒和基因系统来理解该基因的功能、重要性和 这些脑干LepRb神经元的作用机制。 这些研究揭示了脑干中瘦素作用于整体瘦素作用的机制。 神经功能对葡萄糖动态平衡至关重要。这一信息将反过来为 为了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靶点。