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

基本信息

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：
2013
资助国家：
加拿大
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=527969
关键词：
Role pituitary adenylate cyclase activating

项目摘要

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.

通过调节食物摄入和代谢过程消耗的能量消耗的能量来实现能量平衡。在过去的十年中，我们对能量稳态的理解已经大大发展，这是由于了解无调能量平衡的生理后果的愿望而发展。主要是，研究集中在食欲调节中涉及的神经元途径的表征上。能量平衡方程的另一面是能量消耗的荷尔蒙调节，对能量消耗的荷尔蒙调节很少了解。神经肽垂体腺苷酸环化酶激活多肽（PACAP）在整个大脑中表达，在下丘脑中表达高水平，下丘脑是大脑的一个区域，该区域已知与调节能量平衡有关。 PACAP是所有脊椎动物制造的，其蛋白质结构在整个进化过程中都高度保守，这表明它在基本生理过程中起作用。以前，我们生成了无法产生PACAP的小鼠。这些敲除小鼠无法适当调节体温，如果在产后寿命早期21oC死亡的环境温度下升高。但是，如果小鼠在仅3oC的环境温度下升高，则存活率增加到80％。这些研究表明，激素PACAP在温度调节中起作用。 PACAP调节能量平衡的机制仍然未知。我们新生成的数据表明，PACAP敲除小鼠的食欲不受影响，但比野生型对照小鼠更瘦。使用缺乏PACAP和野生型动物的转基因动物，我的旨在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，我们旨在确定神经元得出的PACAP是否负责PACAP敲除小鼠中观察到的热调节问题，并进一步表征哪些表达神经元的PACAP对这些作用负责。重要的是，该提案中提出的研究将促进我们对能量平衡内分泌调节的理解。