Differential AMPK-mediated metabolic regulation observed in hibernation-style polymorphisms in Siberian chipmunks.

Hibernation is a unique physiological phenomenon allowing extreme hypothermia in endothermic mammals. Hypometabolism and hypothermia tolerance in hibernating animals have been investigated with particular interest; recently, studies of cultured cells and manipulation of the nervous system have made it possible to reproduce physiological states related to hypothermia induction. However, much remains unknown about the periodic regulation of hibernation. In particular, the physiological mechanisms facilitating the switch from an active state to a hibernation period, including behavioral changes and the acquisition of hypothermia tolerance remain to be elucidated. AMPK is a protein known to play a central role not only in feeding behavior but also in metabolic regulation in response to starvation. Our previous research has revealed that chipmunks activate AMPK in the brain during hibernation. However, whether AMPK is activated during winter in non-hibernating animals is unknown. Previous comparative studies between hibernating and non-hibernating animals have often been conducted between different species, consequently it has been impossible to account for the effects of phylogenetic differences. Our long-term monitoring of siberian chipmunks, has revealed intraspecific variation between those individuals that hibernate annually and those that never become hypothermic. Apparent differences were found between hibernating and non-hibernating types with seasonal changes in lifespan and blood HP levels. By comparing seasonal changes in AMPK activity between these polymorphisms, we clarified the relationship between hibernation and AMPK regulation. In hibernating types, phosphorylation of p-AMPK and p-ACC was enhanced throughout the brain during hibernation, indicating that AMPK-mediated metabolic regulation is activated. In non-hibernating types, AMPK and ACC were not seasonally activated. In addition, AMPK activation in the hypothalamus had already begun during high Tb before hibernation. Changes in AMPK activity in the brain during hibernation may be driven by circannual rhythms, suggesting a hibernation-regulatory mechanism involving AMPK activation independent of Tb. The differences in brain AMPK regulation between hibernators and non-hibernators revealed in this study were based on a single species thus did not involve phylogenetic differences, thereby supporting the importance of brain temperature-independent AMPK activation in regulating seasonal metabolism in hibernating animals.

AMPK activation, eEF2 inactivation, and reduced protein synthesis in the cerebral cortex of hibernating chipmunks.

During hibernation, mammalian cells are exposed to severe environmental stressors such as low temperature, lowered O2 supply, and glucose deficiency. The cellular metabolic rate is markedly reduced for adapting to these conditions. AMP-activated protein kinase (AMPK) senses the cellular energy status and regulates metabolism. Therefore, we examined AMPK signaling in several brain regions and peripheral tissues in hibernating chipmunk. Eukaryotic elongation factor 2 (eEF2) is a downstream target of AMPK. Phosphorylation of eEF2, indicating its inactivation, is enhanced in the cerebral cortex of hibernating chipmunks. The study indicated that the sequential regulation of AMPK-mammalian target of rapamycin complex 1-eEF2 signaling was altered and protein synthesis ability was reduced in the cerebral cortex of hibernating chipmunks.