Central inhibitory regulation of brown adipose thermogenesis

棕色脂肪产热的中枢抑制调节

• 批准号: 9205275
• 负责人: SHAUN F MORRISON
• 金额: $ 33.69万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205275
• 关键词: Address; Adipose tissue; Adult; Afferent Neurons; Anatomy; Brown Fat; Cell Respiration; Cellular Metabolic Process; Chemoreceptors; Consumption; Cutaneous; Diabetes Mellitus; Dinoprostone; Electrophysiology (science); Energy Metabolism; Exposure to; Fatty acid glycerol esters; Fever; Fiber; Glossopharyngeal nerve structure; Glucose; Glutamates; Homeostasis; Human; Hyperlipidemia; Hypothalamic structure; Impairment; Infection; Lead; Life; Maintenance; Mediating; Metabolic; Metabolic Diseases; Modeling; Nerve; Neural Pathways; Neurons; Neurotransmitters; Nonesterified Fatty Acids; Nucleus solitarius; Obesity; Oxygen; Pathway interactions; Peripheral; Physiological; Population; Process; Production; Pyrogens; Regulation; Research; Research Project Grants; Role; Series; Signal Transduction; Site; Skeletal Muscle; Source; Spinal; Spinal Cord; Stimulus; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; System; TRPV1 gene; Testing; Thermogenesis; Vagus nerve structure; Visceral; blood glucose regulation; carotid sinus; experimental study; improved outcome; in vivo; insight; neural circuit; neurotransmission; paraventricular nucleus; public health relevance; receptor; response; sensor; sensory system

 DESCRIPTION (provided by applicant): The process of metabolizing fat and glucose to produce heat is unique to brown adipose tissue (BAT) (as well as beige adipose tissue), and is under the control of the CNS-generated sympathetic nervous system input to BAT. Although our research has defined the fundamental neural pathways through which thermal and febrile stimuli elicit changes in the sympathetic outflow to BAT, little is known about the neural circuits involve in the inhibitory influences on BAT activity, particularly those arising from sensors of metabolic signals. The findings of a consistent deficit of cold-activated BAT in obese humans and of marked improvements in glucose homeostasis upon BAT activation in models of obesity and diabetes are consistent with an over-active inhibitory regulation of BAT activity in the setting of metabolic disease. The new information from this research could contribute to reversing the detrimental inhibition of BAT activity and improve the outcomes for those with metabolic disease. In the proposed research project, we will determine the neural circuits through which viscerosensory, primarily metabolic, afferent information conveyed via the vagus and glossopharyngeal nerves produces an inhibition of the sympathetic outflow to BAT. Additionally, we seek to understand the roles of CNS regions, including the nucleus of the solitary tract, the ventrolateral medulla and the paraventricular hypothalamus, whose activation can inhibit BAT activity, in the overall inhibitory regulation of BAT activity. We propose a detailed series of in vivo electrophysiological, anatomical, neuropharmacological experiments to address four specific aims that will provide new insights into the inhibitory regulation of BAT thermogenesis. The first aim will address the functional organization of the CNS circuits through which vagal viscerosensory afferents impinging on the NTS can inhibit BAT activity, and will include studies on the region(s) and neurotransmitter systems within the NTS, and localize the likely visceral sources and the classes of relevant physiological stimuli that mediate the potent inhibitory regulation of BAT activity mediated via vagal viscerosensory inputs. We will pursue the pathway between the secondary sensory neurons in NTS and the BAT sympathetic preganglionic neurons in the spinal cord, whose reduced discharge ultimately mediates declines in BAT activity. The second aim will address the functional organization of the CNS circuits through which arterial chemoreceptor afferents in the glossopharyngeal nerve can drive a potent inhibition of BAT activity. In the third aim, we will characterize the role of the several populatins of neurons in the VLM in the inhibitory regulation of BAT activity, including their potential rolesin the BAT inhibitions elicited by vagal, arterial chemoreceptor and PVN activations. The fourth aim will determine is the functional organization of the CNS circuits through which activation of PVN neurons inhibits BAT activity.

 描述（由适用提供）：代谢脂肪和葡萄糖产生热的过程是棕色脂肪组织（BAT）（以及米色脂肪组织）独有的，并且在CNS产生的交感神经系统输入BAT的控制下。尽管我们的研究定义了基本的神经元途径，这些神经元途径通过这些途径引起了蝙蝠的交感神经出口的变化，但对中性电路涉及抑制性影响蝙蝠活性的影响鲜为人知，尤其是那些由代谢信号传感器引起的影响。肥胖人类和糖尿病模型中BAT激活时葡萄糖稳态的持续不足以及葡萄糖稳态的明显改善的发现与蝙蝠活性的过度抑制性调节是一致的。 代谢疾病。这项研究的新信息可能有助于扭转对蝙蝠活性的有害抑制，并改善代谢疾病患者的结果。在拟议的研究项目中，我们将确定通过迷走神经和全藻神经传达的内脏，代谢，传入信息的中性回路产生抑制交感神经流出对BAT的抑制。此外，我们试图了解中枢神经系统区域的作用，包括固体道的核us，腹外侧髓质和旁腔室下丘脑，其激活可以抑制BAT活性的整体抑制作用。我们提出了一系列详细的体内电生理学，解剖学，神经药物实验，以解决四个特定目标，这些目标将为bat热生成的抑制作用提供新的见解。第一个目的将解决CNS电路的功能组织，通过这些组织，撞击NTS上的迷走性内脏传入可以抑制BAT的活动，并包括对NTS中的区域和神经递质系统的研究，并将可能的既有性刺激范围内的生理刺激范围内的生理访问范围定位为中等范围的生理访问，则可以将其定位。我们将追求NTS中的次级感觉神经元与脊髓中的蝙蝠交感神经元之间的途径，其减少的排出最终导致蝙蝠活性的下降。第二个目的将解决中枢神经系统电路的功能组织，通过该电路，ART化学感受器传入中的神经性神经神经中的神经能力可以推动对BAT活性的潜在抑制作用。在第三个目标中，我们将表征神经元在VLM中的几种人群在bat活性（包括其潜力）的抑制调节中的作用。 ROLES在迷走神经，动脉化学感受器和PVN激活引起的BAT抑制作用。第四个目标将确定CNS电路的功能组织，PVN神经元的激活抑制了BAT活性。