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

能量平衡是通过调节食物摄入量和代谢过程消耗的能量来实现的。在过去的十年里，我们对能量平衡的了解有了很大的发展，这是因为我们希望了解不受调节的能量平衡的生理后果。主要的研究集中在涉及食欲调节的神经元通路的特征上。能量平衡方程式的另一边，荷尔蒙对能量消耗的调节，却鲜为人知。神经肽垂体腺苷环化酶激活多肽(PACAP)在整个大脑中都有表达，其中下丘脑的表达水平很高，这是大脑中一个已知参与调节能量平衡的区域。PACAP由所有脊椎动物产生，其蛋白质结构在整个进化过程中高度保守，表明它在基本的生理过程中发挥作用。此前，我们培育了不能产生PACAP的小鼠。这些基因敲除的小鼠不能适当地调节体温，如果在21摄氏度的环境温度下饲养，就会在出生后早期死亡。然而，如果在环境温度仅高3摄氏度的情况下饲养小鼠，存活率将提高到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。我们新产生的数据表明，PACAP基因敲除小鼠的食欲没有受到影响，但比野生型对照小鼠更瘦。利用缺乏PACAP的转基因动物和受到不同环境温度影响的野生型动物，我的目的是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来源的PACAP是否与在PACAP基因敲除小鼠中观察到的体温调节问题有关，并进一步表征哪些表达PACAP的神经元对这些影响负责。重要的是，这项建议中提出的研究将促进我们对能量平衡的内分泌调节的理解。

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.