Brainstem LepRb neurons in the control of metabolism

脑干 LepRb 神经元控制代谢

• 批准号: 8521715
• 负责人: Jonathan Nicholas Flak
• 金额: $ 4.92万
• 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: 2013-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521715
• 关键词: Ablation; Accounting; Adipocytes; Adipose tissue; Affect; Animals; Area; Attention; Behavior Control; Body Weight; Brain; Brain Stem; Brain region; Cell Nucleus; Cholecystokinin; Data; Dependovirus; Development; Diabetes Mellitus; Disasters; Disease; Drug Design; Eating; Endocrine; Energy Metabolism; Epidemic; Exhibits; Functional disorder; Health Expenditures; Homeostasis; Hormones; Hypoglycemia; Hypothalamic structure; Incidence; Knowledge; Lateral; Leptin; Link; Longitudinal Studies; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Midbrain structure; Molecular; Molecular Genetics; Morbid Obesity; Mus; Mutation; Neuraxis; Neurons; Neuropeptides; Neurophysiology - biologic function; Nucleus solitarius; Obesity; Output; Pathogenesis; Phenotype; Physiological; Physiology; Play; Population; Protein Isoforms; Public Health; Regulation; Risk Factors; Role; Satiation; Signal Transduction; Stimulus; Structure of nucleus infundibularis hypothalami; System; Testing; base; blood glucose regulation; energy balance; feeding; glycemic control; hindbrain; insight; leptin receptor; midbrain central gray substance; neural circuit; new therapeutic target; novel; public health relevance; receptor; relating to nervous system; response; therapeutic target; tool; ventromedial hypothalamic nucleus

DESCRIPTION (provided by applicant): Obesity and its metabolic sequelae already underlie hundreds of billions of dollars in annual health care expenditures, and the incidence of obesity is projected to rise to 40% within the next fifteen years. The need to understand the mechanisms controlling energy balance and metabolism thus continues to grow ever more pressing, since this knowledge will be crucial for defining pathogenic mechanisms and for the development of novel therapies. Leptin, an adipocyte-derived hormone secreted in proportion to adipose energy stores, acts via the long isoform of its receptor (LepRb) in the central nervous system to control behavior (e.g., feeding) and physiology (e.g., glucose homeostasis) relevant to energy balance. The central role played by leptin in the control of energy homeostasis suggests the importance of understanding the mechanisms by which leptin mediates its effects. Leptin-responsive (LepRb-expressing) neurons lie in a number of brain regions crucial for the control of metabolic function, including mediobasal hypothalamic (MBH) nuclei (e.g., arcuate nucleus (ARC)) and the brainstem. While MBH leptin action is important and has received considerable attention in recent years, MBH leptin signaling can only account for a fraction of leptin action. The brainstem contains a number of distinct populations of LepRb neurons; the periaqueductal grey (PAG) and lateral parabrachial (lPBN) nuclei contain the largest groups of brainstem LepRb neurons (comparable to LepRb populations in major hypothalamic nuclei). While both of these nuclei contribute to the control of satiety and autonomic function, the roles for LepRb neurons in these regions remain unknown. We found that many PAG/lPBN LepRb neurons contain the neuropeptide, cholecystokinin (CCK), and that the distribution of these LepRbCCK neurons is restricted to the brainstem. Furthermore, our preliminary data reveal roles for these neurons in the control of food intake, body weight, and the glucoprivic response. In this proposal, we will employ a panel of molecular genetic tools to define the regulation and connectivity of brainstem LepRb neurons. Furthermore, we will manipulate the activity of these neurons, as well as their responsiveness to leptin, in order to define their neural and physiologic functions. These studies will provide important insights into novel mechanisms of leptin action in the central nervous system and into the control of energy and glucose homeostasis.

描述(申请人提供)：肥胖症及其代谢后遗症已经成为每年数千亿美元医疗保健支出的基础，肥胖症的发生率是 预计在未来15年内将上升到40%。因此，了解控制能量平衡和新陈代谢的机制的需要变得越来越迫切，因为这一知识将对定义致病机制和开发新的治疗方法至关重要。瘦素是一种脂肪细胞衍生的激素，与脂肪能量储存成比例地分泌，通过其受体(LepRb)的长亚型在中枢神经系统中发挥作用，控制与能量平衡相关的行为(如进食)和生理(如葡萄糖稳态)。瘦素在能量平衡控制中所起的核心作用表明了解瘦素调节其作用的机制的重要性。瘦素反应(LepRb)神经元存在于大脑的许多区域，包括下丘脑内侧基底核(MBH)(如弓状核(ARC))和脑干。虽然MBH瘦素的作用是重要的，并在最近几年受到相当大的关注，但MBH瘦素信号只能占瘦素作用的一小部分。脑干含有许多不同的LepRb神经元；中脑导水管周围灰质(PAG)和臂旁外侧核(LPBN)含有最大的脑干LepRb神经元群(与主要下丘脑核团中的LepRb神经元相似)。虽然这两个核团都有助于控制饱腹感和自主神经功能，但LepRb神经元在这些区域的作用尚不清楚。我们发现许多PAG/lPBN LepRb神经元含有神经肽CCK，并且这些LepRbCCK神经元的分布仅限于脑干。此外，我们的初步数据揭示了这些神经元在控制食物摄入量、体重和葡萄糖反应中的作用。在这项提案中，我们将使用一组分子遗传学工具来定义脑干LepRb神经元的调节和连接。此外，我们将控制这些神经元的活动，以及它们对瘦素的反应，以确定它们的神经和生理功能。这些研究将为瘦素在中枢神经系统中作用的新机制以及对能量和葡萄糖稳态的控制提供重要的见解。