Hibernating mammals actively lower their body temperature to reduce energy expenditure when facing food scarcity¹. This ability to induce a hypometabolic state has evoked great interest owing to its potential medical benefits^2,3. Here we show that a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation. In this state, although body temperature and levels of oxygen consumption are kept very low, the ability to regulate metabolism still remains functional, as in hibernation⁴. There was no obvious damage to tissues and organs or abnormalities in behaviour after recovery from this state. Our findings could enable the development of a method to induce a hibernation-like state, which would have potential applications in non-hibernating mammalian species including humans.

Some mammals enter a hypometabolic state either daily torpor (minutes to hours in length) or hibernation (days to weeks), when reducing metabolism would benefit survival. Hibernators demonstrate deep torpor by reducing both the sensitivity (H) and the theoretical set-point temperature (T_R) of the thermogenesis system, resulting in extreme hypothermia close to ambient temperature. However, these properties during daily torpor remain poorly understood due to the very short steady state of the hypometabolism and the large variation among species and individuals. To overcome these difficulties in observing and evaluating daily torpor, we developed a novel torpor-detection algorithm based on Bayesian estimation of the basal metabolism of individual mice. Applying this robust method, we evaluated fasting induced torpor in various ambient temperatures (T_As) and found that H decreased 91.5% during daily torpor while T_R only decreased 3.79 °C in mice. These results indicate that thermogenesis during daily torpor shares a common property of sensitivity reduction with hibernation while it is distinct from hibernation by not lowering T_R. Moreover, our findings support that mice are suitable model animals to investigate the regulation of the heat production during active hypometabolism, thus suggesting further study of mice may provide clues to regulating hypometabolism in mammals.

Mice enter an active hypometabolic state, called daily torpor when they experience a lowered caloric intake under cold ambient temperature. During torpor, the oxygen consumption rate in some animals drops to less than 30% of the normal rate without harming the body. This safe but severe reduction in metabolism is attractive for various clinical applications; however, the mechanism and molecules involved are unclear. Therefore, here we systematically analyzed the gene expression landscape on the level of the RNA transcription start sites in mouse skeletal muscles under various metabolic states to identify torpor-specific transcribed regulatory patterns. We analyzed the soleus muscles from 38 mice in torpid and non-torpid conditions and identified 287 torpor-specific promoters out of 12,862 detected promoters. Furthermore, we found that the transcription factor ATF3 is highly expressed during torpor deprivation and its binding motif is enriched in torpor-specific promoters. Atf3 was also highly expressed in the heart and brown adipose tissue during torpor and systemically knocking out Atf3 affected the torpor phenotype. Our results demonstrate that mouse torpor combined with powerful genetic tools is useful for studying active hypometabolism.

During hibernation, some mammals show low body temperatures (<10°C). Tissues from hibernators exhibit cold resistance even when the animal is not hibernating. Mice can also enter hypothermic fasting-induced torpor (FIT), but the cold resistance of FIT has never been related to their tissues. Here, we show that an inbred mouse STM2 exhibits lower body temperature during FIT than C57BL/6J or MYS/Mz. Thus, STM2 resists the cold more than other strains. Analysis of strain-specific mouse embryonic stem (ES) cells shows that STM2 ES cells are more cold-resistant than others and rely on the oxidative phosphorylation (OXPHOS) pathway but respire independently of the electron transfer chain complex I in the cold. We also found that the liver of STM2 uses OXPHOS more in cold than other strains. This study demonstrates that an organismal phenotype associated with torpor can be effectively studied in an in vitro setup using mouse cells.

To the best of our knowledge, this is the first positron emission tomography (PET) study using a Q neuron-induced hypothermia and hypometabolism (QIH) mouse model, which is a synthetic hibernation-like state triggered by neural stimulation. We investigated changes in the in vivo dynamics of various essential nutrients and bioactive substances during hibernation using three types of metabolic probes: the glucose derivative [¹⁸F]FDG (fluorodeoxyglucose), amino acid derivative L-m-[¹¹C]tolylalanine, and vitamin B₁ derivative [¹¹C]thiamine. We found that cardiac glucose metabolism was significantly reduced during the QIH state. Both vitamin B₁ and the amino acid derivatives exhibited rapid systemic distribution immediately after intravenous administration, which may indicate increased translocation into tissues based on altered circulatory dynamics or vascular wall properties. We also found that the proliferation of subcutaneously inoculated tumors was dramatically suppressed by QIH. Recently, hibernation has increasingly attracted attention because of its advantages, including reduced oxygen and energy consumption, that can mitigate organ damage. Notably, hibernation-like states may have potential applications in emergency and critical care medicine. Therefore, the advancement of hibernation research using QIH models and highlighted the potential of hibernation-like states for novel applications in cancer therapy and drug delivery.