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

能量稳态是通过平衡通过食物摄入消耗的能量和通过静息代谢率、身体活动和体温调节等过程诱导的代谢途径消耗的能量来实现的。在过去的20年里，关于调节能量平衡的神经元通路的知识得到了很大的发展，这是由于人们希望了解能量平衡失调的后果。我的研究项目旨在加强我们对激素如何以及哪些激素在调节能量平衡中发挥作用的理解。具体来说，我们正在研究神经肽，垂体腺苷酸环化酶激活多肽（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产生热量的通路。使用缺乏PACAP的小鼠模型，我们已经证明，如果缺乏PACAP，这种正常的冷适应就不会发生，这表明PACAP对棕色脂肪的适应性产热调节至关重要。我们假设下丘脑中表达pacap的神经元调节激活棕色脂肪产热的交感神经。利用分子生物学、生理学和组织学技术，我们旨在表征PACAP和PACAP受体在这些神经元中的表达，并了解集中表达的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如何调节产热的机制理解，从而增强我们对激素如何调节能量平衡的认识。

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.