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

能量平衡是通过将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，对调节能量平衡的神经元通路的了解有了很大的进展，这是由于人们希望了解调节代谢的复杂生理。神经元通路利用一种叫做激素（或神经肽）的化学信使在大脑内部以及大脑和周围器官之间进行交流，以调节能量的消耗和消耗。控制食欲的特定途径已经被很好地描述了；然而，参与调节能量消耗的途径（基础代谢率、产热和身体活动）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，还有许多其他的激素，它们在能量平衡中的作用或相互作用尚不清楚，这些基本知识对于全面理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是一种存在于所有脊椎动物体内的古老神经肽。它在协调身体对压力的反应中起着关键作用，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，它激活或抑制恢复平衡的途径。我的研究已经确定了PACAP在冷应激反应中通过调节产热来恢复能量平衡的作用。产热是一种能量燃烧途径，在寒冷暴露和过度进食的情况下被开启。寒战产热发生在骨骼肌中，是对急性感冒的反应。在长期的寒冷环境中，一种特殊类型的脂肪组织，即棕色脂肪，会启动一种叫做适应性产热的过程。除了人类婴儿和啮齿类动物，棕色脂肪存在于所有哺乳动物，包括成年人，并在维持生命的能量平衡中起着重要作用。本研究旨在描述PACAP及其受体如何通过大脑、交感神经系统（SNS）的“战斗或逃跑”通路和棕色脂肪对冷应激的反应来调节产热，探索PACAP如何在热应激时在热调节级联（脑-SNS-棕色脂肪）的各个水平上起作用，重新平衡能量代谢。所产生的知识将阐明PACAP如何启动和调节对冷应激的生理反应，阐明热生理和内分泌生理学的未知方面。这些生理知识的基础构建块可以应用于不同的科学研究领域，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。

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.