Endocrine regulation of thermogenesis: role of pituitary adenylate cylase-activating polypeptide (PACAP)

能量平衡是通过平衡食物摄入所消耗的能量和由静息代谢率、体力活动和体温调节等过程引起的代谢途径消耗的能量来实现的。在过去的20年里，由于渴望了解能量平衡失调的后果，对调节能量平衡的神经元通路的知识有了很大的发展。我的研究计划旨在加强我们对荷尔蒙如何以及哪些激素在调节能量平衡中发挥作用的理解。具体地说，我们正在研究神经肽--脑下垂体腺苷环化酶激活多肽(PACAP)在体温调节中的作用。PACAP在大脑中控制食欲和能量消耗的区域表达，包括下丘脑。有证据表明，下丘脑产生的PACAP可以通过激活棕色脂肪中的神经元活动来诱导产热。棕色脂肪是一种特殊类型的脂肪，当被激活时，会产生热量。正常情况下，老鼠和其他哺乳动物对寒冷的反应是通过交感神经系统激活棕色脂肪中的产热途径。使用PACAP缺乏的小鼠模型，我们已经证明，如果没有PACAP，这种正常的冷适应不会发生，这表明PACAP对于调节棕色脂肪的适应性产热至关重要。我们假设，下丘脑中表达PACAP的神经元调节交感神经，从而激活棕色脂肪中的产热。我们利用分子生物学、生理学和组织学的技术，研究PACAP及其受体在这些神经元中的表达，以了解PACAP在调节适应性产热中的功能意义。这项工作的结果将提供对PACAP如何调节产热的机械理解，从而增强我们对激素如何调节能量平衡的了解。

Energy homeostasis is achieved by balancing the amount of energy consumed through food intake and expended by metabolic pathways induced by processes such as resting metabolic rate, physical activity and thermoregulation. In the past 20 years, knowledge of neuronal pathways regulating energy balance has developed substantially driven by a desire to understand consequences of dysregulated energy balance. My program of research aims to enhance our understanding of how and which hormones play a role in regulating energy balance. Specifically we are examining the role of the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP) in thermoregulation. PACAP is expressed in regions of the brain that control appetite and energy expenditure, including the hypothalamus. There is evidence to suggest that PACAP produced in the hypothalamus can induce thermogenesis by activating neuronal activity in brown fat, a specialized type of fat that, when activated, produces heat. Normally mice and other mammals respond to cold exposure by activating heat-producing pathways in brown fat via the sympathetic nervous system. Using a mouse model that is deficient in PACAP, we have shown that this normal adaptation to cold does not occur if PACAP is absent, indicating PACAP is critical for the regulation of adaptive thermogenesis in brown fat. We hypothesize that PACAP-expressing neurons in the hypothalamus regulate sympathetic nerves that activate thermogenesis in brown fat. Using techniques in molecular biology, physiology and histology we aim to characterize the expression of PACAP and the PACAP receptor in these neurons and understand the functional significance of centrally expressed PACAP in regulating adaptive thermogenesis. Results from this work will provide a mechanistic understanding of how PACAP regulates thermogenesis, thus enhancing our knowledge of how hormones regulate energy balance.