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

产热的内分泌调节：垂体腺苷酸环化酶激活多肽（PACAP）的作用

• 批准号: RGPIN-2015-06146
• 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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613973
• 关键词: Endocrine; regulation; thermogenesis; role; pituitary

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.

能量稳态是通过平衡食物摄入消耗的能量和静息代谢率、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，由于了解能量平衡失调的后果，人们对调节能量平衡的神经通路的了解得到了极大的发展。我的研究计划旨在增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 在控制食欲和能量消耗的大脑区域表达，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生热作用，棕色脂肪是一种特殊类型的脂肪，在激活时会产生热量。通常，小鼠和其他哺乳动物通过交感神经系统激活棕色脂肪中的产热途径来应对寒冷暴露。使用 PACAP 缺陷的小鼠模型，我们发现，如果 PACAP 缺失，这种对寒冷的正常适应就不会发生，这表明 PACAP 对于调节棕色脂肪的适应性生热作用至关重要。我们假设下丘脑中表达 PACAP 的神经元调节交感神经，从而激活棕色脂肪的生热作用。利用分子生物学、生理学和组织学技术，我们的目标是表征这些神经元中 PACAP 和 PACAP 受体的表达，并了解中心表达的 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 如何调节生热作用的机制理解，从而增强我们对激素如何调节能量平衡的了解。