Department of Cell Biology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Eur J Pharmacol. 2013 Nov 5;719(1-3):137-144. doi: 10.1016/j.ejphar.2013.07.027. Epub 2013 Jul 25.
The neural substrate of adaptive thermoregulation in mice lacking both brain-type creatine kinase isoforms is further investigated. The cytosolic brain-type creatine kinase (CK-B) and mitochondrial ubiquitous creatine kinase (UbCKmit) are expressed in neural cells throughout the central and peripheral nervous system, where they have an important role in cellular energy homeostasis. Several integral functions appear altered when creatine kinases are absent in the brain (Jost et al., 2002; Streijger et al., 2004, 2005), which has been explained by inefficient neuronal transmission. The CK--/-- double knockout mice demonstrate every morning a body temperature drop of ~1.0 °C, and they have impaired thermogenesis, as revealed by severe hypothermia upon cold exposure. This defective thermoregulation is not associated with abnormal food intake, decreased locomotive activity, or increased torpor sensitivity. Although white and brown adipose tissue fat pads are diminished in CK--/-- mice, intravenous norepinephrine infusion results in a normal brown adipose tissue response with increasing core body temperatures, indicating that the sympathetic innervation functions correctly (Streijger et al., 2009). This study revealed c-fos changes following a cold challenge, and that neuropeptide Y levels were decreased in the paraventricular nucleus of wildtype, but not CK--/--, mice. A reduction in hypothalamic neuropeptide Y is coupled to increased uncoupling protein 1 expression in brown adipose tissue, resulting in thermogenesis. In CK--/-- mice the neuropeptide Y levels did not change. This lack of hypothalamic plasticity of neuropeptide Y might be the result of inefficient neuronal transmission or can be explained by the previous observation of reduced circulating levels of leptin in CK--/-- mice.
进一步研究了缺乏两种脑型肌酸激酶同工酶的小鼠适应性体温调节的神经基质。细胞质脑型肌酸激酶（CK-B）和线粒体普遍肌酸激酶（UbCKmit）在中枢和外周神经系统的神经细胞中表达，在那里它们在细胞能量稳态中发挥重要作用。当大脑中缺乏肌酸激酶时，几个整体功能似乎发生了改变（Jost 等人，2002 年；Streijger 等人，2004 年，2005 年），这可以通过神经元传递效率低下来解释。CK--/--双敲除小鼠每天早上体温下降约 1.0°C，并且它们的产热受到损害，如在寒冷暴露下出现严重的低体温所揭示的那样。这种有缺陷的体温调节与异常的食物摄入、运动活性降低或增加的休眠敏感性无关。尽管 CK--/--小鼠的白色和棕色脂肪组织脂肪垫减少，但静脉内去甲肾上腺素输注导致正常的棕色脂肪组织反应，核心体温升高，表明交感神经支配功能正常（Streijger 等人，2009 年）。这项研究揭示了冷挑战后的 c-fos 变化，并且神经肽 Y 水平在野生型的室旁核中降低，但在 CK--/--小鼠中没有降低。下丘脑神经肽 Y 的减少与棕色脂肪组织中解偶联蛋白 1表达的增加相关，导致产热。在 CK--/--小鼠中，神经肽 Y 水平没有变化。这种神经肽 Y 的下丘脑可塑性缺乏可能是神经元传递效率低下的结果，也可以用 CK--/--小鼠中循环瘦素水平降低的先前观察结果来解释。
