CO 2 and active metabolic suppression in hibernation: mechanisms for natural torpor induction

Hibernating mammals exhibit remarkable reductions in metabolism, body temperature, and physical activity when faced with limited resources. Harnessing this hibernation phenotype has long been pursued for potential medical applications, spanning from obesity treatment to emergency critical care on Earth and even extended space travel. Yet, the precise biological mechanisms that enable natural hibernators to enter torpor remain incompletely understood. Recent progress in synthetic torpor techniques has provided valuable insights into how torpor may be induced, though many approaches still fall short of replicating the profound metabolic suppression characteristic of true hibernation. Multiple studies have identified a link between CO 2 dynamics and active metabolic suppression during torpor, showing that abrupt increases in CO 2 retention coincide with rapid, temperature-independent reductions in metabolism at the onset of torpor. Our recent work demonstrated that regulated changes in ventilation enable animals to deliberately retain or expel excess CO 2 at the onset of torpor entry and during arousal. We propose that the regulation of CO 2 within blood and tissues plays a pivotal role in driving the active metabolic suppression characteristic of hibernating species. In the present study, we subjected thirteen-lined ground squirrels transitioning into or out of torpor to elevated environmental CO 2 concentrations (3%, 5%, and 7%) to assess whether hypercapnia could enhance metabolic suppression during entrance, and impede the subsequent rise in metabolism during arousal from torpor. Hypercapnia was applied both at the onset of torpor entry and arousal, as well as two hours prior to these state transitions. Metabolic and temperature responses were monitored throughout to evaluate whether CO 2 flux plays a critical role in regulating the torpor–arousal cycle. Our findings revealed significant effects of hypercapnia on metabolic suppression and torpor dynamics. When high CO 2 (5% and 7%) was introduced at the onset of torpor entry, metabolism declined more rapidly, shortening overall entrance by approximately 40 minutes. During arousal, hypercapnic exposure reduced the peak metabolic rate by about 20%, but did not otherwise alter the progression of recovery. Pre-exposure to hypercapnia prior to torpor entry produced no additional changes in the likelihood of entering torpor or in the degree of metabolic suppression beyond those observed when exposure occurred at torpor onset. In contrast, pre-exposure to hypercapnia before arousal completely inhibited recovery, with animals remaining in torpor until CO 2 levels were normalized. These results underscore a critical role of CO 2 regulation in the torpor–arousal cycle, although the precise mechanisms by which CO 2 modulates metabolism remain unresolved. Funded by NIH R01HL142752 (JJW and TLB) and NSERC 22R87150 (WKM). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.