Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado;
Department of Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado; Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, Colorado; and.
Physiol Genomics. 2014 May 15;46(10):348-61. doi: 10.1152/physiolgenomics.00190.2013. Epub 2014 Mar 18.
Small-bodied hibernators partition the year between active homeothermy and hibernating heterothermy accompanied by fasting. To define molecular events underlying hibernation that are both dependent and independent of fasting, we analyzed the liver proteome among two active and four hibernation states in 13-lined ground squirrels. We also examined fall animals transitioning between fed homeothermy and fasting heterothermy. Significantly enriched pathways differing between activity and hibernation were biased toward metabolic enzymes, concordant with the fuel shifts accompanying fasting physiology. Although metabolic reprogramming to support fasting dominated these data, arousing (rewarming) animals had the most distinct proteome among the hibernation states. Instead of a dominant metabolic enzyme signature, torpor-arousal cycles featured differences in plasma proteins and intracellular membrane traffic and its regulation. Phosphorylated NSFL1C, a membrane regulator, exhibited this torpor-arousal cycle pattern; its role in autophagosome formation may promote utilization of local substrates upon metabolic reactivation in arousal. Fall animals transitioning to hibernation lagged in their proteomic adjustment, indicating that the liver is more responsive than preparatory to the metabolic reprogramming of hibernation. Specifically, torpor use had little impact on the fall liver proteome, consistent with a dominant role of nutritional status. In contrast to our prediction of reprogramming the transition between activity and hibernation by gene expression and then within-hibernation transitions by posttranslational modification (PTM), we found extremely limited evidence of reversible PTMs within torpor-arousal cycles. Rather, acetylation contributed to seasonal differences, being highest in winter (specifically in torpor), consistent with fasting physiology and decreased abundance of the mitochondrial deacetylase, SIRT3.
小型冬眠动物在活跃的恒温状态和伴有禁食的冬眠异温状态之间分配时间。为了定义依赖于和独立于禁食的冬眠相关的分子事件，我们分析了 13 线地松鼠的两种活跃状态和四种冬眠状态之间的肝脏蛋白质组。我们还研究了从摄食的恒温状态过渡到禁食的异温状态的秋季动物。在活动和冬眠之间差异显著的富集途径偏向于代谢酶，与伴随禁食生理学的燃料转变一致。尽管代谢重编程以支持禁食在这些数据中占主导地位，但唤醒（复温）动物在冬眠状态中具有最独特的蛋白质组。而不是主导的代谢酶特征，蛰伏-唤醒周期的特征在于血浆蛋白和细胞内膜运输及其调节的差异。磷酸化的 NSFL1C，一种膜调节剂，表现出这种蛰伏-唤醒周期模式；它在自噬体形成中的作用可能在唤醒时的代谢再激活过程中促进利用局部底物。过渡到冬眠的秋季动物在其蛋白质组调整方面滞后，表明肝脏对冬眠的代谢重编程的反应性大于预备性。具体而言，蛰伏对秋季肝脏蛋白质组的影响很小，与营养状况的主导作用一致。与我们预测的通过基因表达重新编程活动与冬眠之间的过渡，然后通过翻译后修饰（PTM）重新编程冬眠内的过渡不同，我们发现蛰伏-唤醒周期内可逆转的 PTM 证据非常有限。相反，乙酰化作用对季节性差异有贡献，在冬季（特别是在蛰伏中）最高，与禁食生理学和线粒体去乙酰化酶 SIRT3 的丰度降低一致。
