Central inhibitory regulation of brown adipose thermogenesis

 描述（由申请人提供）：代谢脂肪和葡萄糖以产生热量的过程是棕色脂肪组织（BAT）（以及米色脂肪组织）所特有的，并且受CNS产生的交感神经系统输入BAT的控制。虽然我们的研究已经确定了基本的神经通路，通过这些通路，热和发热刺激引起交感神经流出BAT的变化，但对BAT活性的抑制影响所涉及的神经回路知之甚少，特别是那些由代谢信号传感器引起的神经回路。在肥胖人群中冷激活BAT的一致缺陷以及在肥胖和糖尿病模型中BAT激活后葡萄糖稳态的显著改善的发现与在肥胖和糖尿病背景下BAT活性的过度活性抑制性调节一致。 代谢性疾病这项研究的新信息可能有助于逆转BAT活性的有害抑制，并改善代谢疾病患者的预后。 在拟议的研究项目中，我们将确定内脏感觉，主要是代谢，传入信息通过迷走神经和舌咽神经传递的神经回路产生抑制交感神经流出BAT。此外，我们试图了解中枢神经系统的区域，包括孤束核，腹外侧延髓和室旁下丘脑，其激活可以抑制BAT活性，在BAT活性的整体抑制性调节的作用。我们提出了一系列详细的体内电生理，解剖，神经药理学实验，以解决四个具体的目标，将提供新的见解BAT产热抑制调节。第一个目标将解决中枢神经系统回路的功能组织，通过迷走内脏感觉传入撞击NTS可以抑制BAT活动，并将包括对NTS内的区域和神经递质系统的研究，并定位可能的内脏来源和相关生理刺激的类别，这些刺激介导通过迷走内脏感觉输入介导的BAT活动的有效抑制调节。我们将追踪NTS中的次级感觉神经元和脊髓中的BAT交感节前神经元之间的通路，其减少的放电最终介导BAT活性的下降。第二个目标将解决中枢神经系统回路的功能组织，通过该中枢神经系统回路，舌咽神经中的动脉化学感受器传入可以驱动BAT活性的有效抑制。在第三个目标中，我们将描述VLM中的几个神经元群体在BAT活性的抑制性调节中的作用，包括它们在由迷走神经、动脉化学感受器和PVN激活引起的BAT抑制中的潜在作用。第四个目标是确定中枢神经系统回路的功能组织，通过该中枢神经系统回路，PVN神经元的激活抑制BAT活性。

 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.