Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade

能量代谢的神经内分泌调节：垂体腺苷酸环化酶激活多肽（PACAP）在温度调节级联中的作用

• 批准号: RGPIN-2021-04040
• 负责人: Gray, Sarah
• 金额: $ 2.04万
• 依托单位: University of Northern British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742829
• 关键词: Neuroendocrine; regulation; energy; metabolism; role

Energy balance is achieved by matching the amount of energy consumed, with the amount of energy expended. In the past 25 years, knowledge of neuronal pathways regulating energy balance has advanced substantially, driven by a desire to understand the complex physiology regulating metabolism. Neuronal pathways utilize chemical messengers called hormones (or neuropeptides) that communicate within the brain, and between the brain and the peripheral organs, to regulate how much energy is consumed and expended. The specific pathways that control appetite are well characterized; however, the pathways involved in regulating energy expenditure (basal metabolic rate, thermogenesis and physical activity) are still being realized. Some well-known hormones that influence energy balance include thyroid hormones, leptin and cortisol. There are many other hormones, however, whose actions or interactions in energy balance are not yet clear - basic knowledge of which is critical to a comprehensive understanding of energy balance in animal physiology. In my lab, we study a hormone called pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is an ancient neuropeptide found in all vertebrates. It plays a critical role in coordinating the body's response to stress, activating or inhibiting pathways to restore balance when physiological processes have been tipped out-of-balance by stressors such as danger, starvation, injury/infection or cold. My research has identified a role for PACAP in restoring energy balance in response to cold stress by regulating thermogenesis. Thermogenesis is an energy burning pathway that is turned on in response to cold exposure and overfeeding. Shivering thermogenesis occurs in skeletal muscle in response to acute cold. In long-term cold exposure, a process called adaptive thermogenesis is turned on in a specialized type of adipose tissue, brown fat. In addition to human infants and rodents, brown fat is present in all mammals, including adult humans, and plays a significant role in maintaining energy balance throughout life. This proposal aims to characterize how PACAP and its receptors regulate thermogenesis through actions in the brain, in the "fight or flight" pathways of the sympathetic nervous system (SNS) and in brown fat in response to cold stress, exploring how PACAP acts at each level of the thermoregulatory cascade (brain-SNS-brown fat) to re-balance energy metabolism in times of thermogenic stress. Knowledge generated will elucidate how PACAP initiates and modulates the physiological response to cold stress, illuminating unknown aspects thermogenic and endocrine physiology. These foundational building blocks of physiological knowledge can be applied to diverse areas of scientific study including biological studies related to changes in body temperature such as hibernation and fever, therapeutic targeting of hormone receptors and human/animal pathophysiology of energy metabolism.

能量平衡是通过使消耗的能量与消耗的能量相匹配来实现的。在过去的25年里，神经元通路调节能量平衡的知识有了很大的进步，由希望了解复杂的生理调节代谢。神经元通路利用称为激素（或神经肽）的化学信使在大脑内以及大脑和外周器官之间进行通信，以调节消耗和消耗多少能量。控制食欲的特定途径已得到很好的表征;然而，参与调节能量消耗（基础代谢率，产热和体力活动）的途径仍在实现中。一些众所周知的影响能量平衡的激素包括甲状腺激素、瘦素和皮质醇。然而，还有许多其他激素，它们在能量平衡中的作用或相互作用尚不清楚-这方面的基本知识对于全面了解动物生理学中的能量平衡至关重要。在我的实验室里，我们研究一种叫做垂体腺苷酸环化酶激活多肽（PACAP）的激素。PACAP是一种古老的神经肽，存在于所有脊椎动物中。它在协调身体对压力的反应，激活或抑制通路以恢复平衡方面起着关键作用，当生理过程因危险，饥饿，受伤/感染或寒冷等压力因素而失去平衡时。我的研究已经确定了PACAP在恢复能量平衡中的作用，通过调节产热来应对冷应激。 产热作用是一种能量燃烧途径，在冷暴露和过度喂养时被打开。骨骼肌对急性寒冷的反应是颤抖性产热。在长期的冷暴露中，一种称为适应性产热的过程在一种特殊类型的脂肪组织，棕色脂肪中被打开。除了人类婴儿和啮齿动物，棕色脂肪存在于所有哺乳动物中，包括成年人，并在维持整个生命的能量平衡方面发挥重要作用。该提案旨在描述PACAP及其受体如何通过大脑中的作用调节产热，在交感神经系统（SNS）的“战斗或逃跑”途径和棕色脂肪中响应冷应激，探索PACAP如何在温度调节级联（大脑-SNS-棕色脂肪）的每个水平上发挥作用，以重新平衡产热应激时的能量代谢。 产生的知识将阐明PACAP如何启动和调节冷应激的生理反应，照亮未知的方面产热和内分泌生理学。这些生理学知识的基础构建模块可以应用于科学研究的各个领域，包括与体温变化相关的生物学研究，如冬眠和发烧，激素受体的治疗靶向和人类/动物能量代谢的病理生理学。