Molecular signatures of mammalian hibernation: comparisons with alternative phenotypes

Abstract

Background: Mammalian hibernators display phenotypes similar to physiological responses to calorie restriction and fasting, sleep, cold exposure, and ischemia-reperfusion in non-hibernating species. Whether biochemical changes evident during hibernation have parallels in non-hibernating systems on molecular and genetic levels is unclear.

Results: We identified the molecular signatures of torpor and arousal episodes during hibernation using a custom-designed microarray for the Arctic ground squirrel (Urocitellus parryii) and compared them with molecular signatures of selected mouse phenotypes. Our results indicate that differential gene expression related to metabolism during hibernation is associated with that during calorie restriction and that the nuclear receptor protein PPARα is potentially crucial for metabolic remodeling in torpor. Sleep-wake cycle-related and temperature response genes follow the same expression changes as during the torpor-arousal cycle. Increased fatty acid metabolism occurs during hibernation but not during ischemia-reperfusion injury in mice and, thus, might contribute to protection against ischemia-reperfusion during hibernation.

Conclusions: In this study, we systematically compared hibernation with alternative phenotypes to reveal novel mechanisms that might be used therapeutically in human pathological conditions.

Figure 1

Venn diagram of differentially expressed genes during hibernation. 916, 823, and 383 genes were differentially expressed in T vs. P, A vs. P, and T vs. A comparisons, respectively. T: torpor; A: arousal episodes; P: post-reproduction.

Figure 2

Distribution of circadian phases of differentially expressed genes in torpor vs. arousal episodes. Open and filled bars symbolize light (mice are asleep) and dark (mice are active) phases. Circadian peaks of genes that were over-expressed in torpor appeared mostly in the light phase (A) and circadian peaks of genes that were under-expressed in torpor appeared mostly in the dark phase (B). T: torpor; A: arousal episodes.

Figure 3

Patterns of gene expression in ischemia-reperfusion (CN-IS-RP) and hibernation (P-T-A). The expression values were normalized to (-1,1) in the ischemia-reperfusion (A) and hibernation datasets (B). Gene expression trends were clustered into nine patterns by self-organizing mapping. The numbers of genes in each pattern are shown on the top of the grids. The patterns that contain the most genes are in the top left and bottom right of each map. One of the major patterns shared between ischemia-reperfusion and hibernation is the high-low-low pattern (A and B, top left). One major difference between ischemia-reperfusion and hibernation is that hibernation exhibits a low-high-high pattern (B, right bottom). CN: control; IS: ischemia; RP: reperfusion; T: torpor; A: arousal episodes; P: post-reproduction.

Figure 4

Heat maps of genes in the protein-ubiquitination pathway and fatty acid metabolism during ischemia-reperfusion and hibernation. Genes involved in the protein-ubiquitination pathway decrease in expression during ischemia-reperfusion (A) but not during hibernation (B). Genes involved in fatty acid metabolism displayed lower expressions in ischemia-reperfusion (C) but greater expressions in torpor than in either arousal episodes or post-reproduction (D). CN: control; IS: ischemia; RP: reperfusion; T: torpor; A: arousal episodes; P: post-reproduction.

Figure 5

Comparison of molecular signatures during hibernation to non-hibernation physiological conditions. (A) The most significant molecular signatures during hibernation in comparison with calorie restriction, PPARα knockout, sleep deprivation, and cold exposure. (B) Highlighted genes exhibited reasonable changes in direction in physiological conditions and hibernation (opposite in PPARα knockout and T vs. P, opposite in sleep deprivation and T vs. A, consistent in calorie restriction and hibernation signatures, consistent in cold exposure and hypothermia signatures). The arc lines divide the different hibernation signatures (T vs. P, T vs. A, and A vs. P). The color of the gene indicates the condition it belongs to. Genes with multiple colors are differentially expressed in more than one physiological condition. The gene sizes were scaled to log2 fold-changes of genes in hibernation. T: torpor; A: arousal episodes; P: post-reproduction.