Role of pituitary adenylate cyclase-activating polypeptide (PACAP) in energy balance

垂体腺苷酸环化酶激活多肽（PACAP）在能量平衡中的作用

• 批准号: 355956-2008
• 负责人: Gray, Sarah
• 金额: $ 2.35万
• 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: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=482959
• 关键词: Role; pituitary; adenylate; cyclase; activating

Energy balance is achieved by regulating the amount of energy consumed through food intake and energy expended by metabolic processes. Our understanding of energy homeostasis has developed substantially in the past decade driven by a desire to understand the physiological consequences of disregulated energy balance. Predominantly, research has focused on the characterization of neuronal pathways involved in appetite regulation. The other side of the energy balance equation, hormonal regulation of energy expenditure, is poorly understood. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is expressed throughout the brain with a high level of expression in the hypothalamus, a region of the brain known to be involved in regulating energy balance. PACAP is made by all vertebrates and its protein structure has been highly conserved throughout evolution, suggesting it plays a role in fundamental physiological processes. Previously we generated mice that are unable to produce PACAP. These knockout mice are unable to regulate body temperature appropriately and if raised at an ambient temperature of 21oC die early in postnatal life. If however the mice are raised at an ambient temperature of only 3oC higher, survival is increased to 80%. These studies demonstrated that the hormone PACAP plays a role in thermoregulation. The mechanism by which PACAP regulates energy balance is still unknown. Our newly generated data suggests appetite is not affected in PACAP knockout mice, yet are leaner than wildtype control mice. Using transgenic animals that lack PACAP and wildtype animals subjected to different environmental temperatures I aim to elucidate the physiological role of the highly conserved neuropeptide PACAP in thermoregulation and energy balance. Additionally we aim to establish if neuronally derived PACAP is responsible for the thermoregulatory problems observed in PACAP knockout mice and to further characterize which PACAP expressing neurons are responsible for these effects. Importantly, studies put forth in this proposal will advance our understanding of the endocrine regulation of energy balance.

能量平衡是通过调节通过食物摄入消耗的能量和代谢过程消耗的能量来实现的。我们对能量稳态的理解在过去十年中有了很大的发展，这是由于我们希望理解能量平衡失调的生理后果。主要的研究集中在参与食欲调节的神经元通路的表征上。能量平衡方程的另一边，即激素对能量消耗的调节，人们知之甚少。脑垂体腺苷酸环化酶激活多肽（PACAP）在整个大脑中表达，其中下丘脑的表达水平较高，下丘脑是大脑中调节能量平衡的区域。所有脊椎动物都有PACAP，其蛋白结构在整个进化过程中高度保守，表明它在基本生理过程中发挥作用。之前我们培育的小鼠不能产生PACAP。这些基因敲除小鼠不能适当地调节体温，如果在21℃的环境温度下饲养，会在出生后早期死亡。然而，如果小鼠在仅高出3摄氏度的环境温度下饲养，存活率将增加到80%。这些研究表明，激素PACAP在体温调节中起作用。PACAP调节能量平衡的机制尚不清楚。我们新生成的数据表明，PACAP基因敲除小鼠的食欲不受影响，但比野生型对照小鼠更瘦。利用缺乏PACAP的转基因动物和野生型动物，在不同环境温度下阐明高度保守的神经肽PACAP在体温调节和能量平衡中的生理作用。此外，我们的目标是确定神经源性PACAP是否导致了在PACAP基因敲除小鼠中观察到的体温调节问题，并进一步表征哪些表达PACAP的神经元导致了这些影响。重要的是，本提案提出的研究将促进我们对内分泌调节能量平衡的理解。