During hibernation, animals cycle between torpor and arousal. These cycles involve
dramatic but poorly understood mechanisms of dynamic physiological regulation at the
level of gene expression. Each cycle, Brown Adipose Tissue (BAT) drives periodic
arousal from torpor by generating essential heat. We applied digital transcriptome
analysis to precisely timed samples to identify molecular pathways that underlie the
intense activity cycles of hibernator BAT. A cohort of transcripts increased during
torpor, paradoxical because transcription effectively ceases at these low
temperatures. We show that this increase occurs not by elevated transcription but
rather by enhanced stabilization associated with maintenance and/or extension of long
poly(A) tails. Mathematical modeling further supports a temperature-sensitive
mechanism to protect a subset of transcripts from ongoing bulk degradation instead of
increased transcription. This subset was enriched in a C-rich motif and genes
required for BAT activation, suggesting a model and mechanism to prioritize
translation of key proteins for thermogenesis.
Many mammals hibernate to avoid food scarcity and harsh conditions during winter.
Hibernation involves entering a state called torpor, which drastically reduces the
amount of energy used by the body. During torpor, body temperature also decreases.
This is particularly exemplified in ground squirrels, whose body temperature can
hover at just above or even below the point of freezing. However, hibernating mammals
cannot remain in this state continuously over the months of hibernation but instead
cycle between bouts of torpor lasting for 1–3 weeks and brief periods of
‘arousal’ lasting between 12–24 hr, during which their body
rapidly warms up.
The heat required to start warming up the hibernator is generated from a specialized
form of fat called brown adipose tissue. Normally, the bursts of metabolic activity
that are required to create this heat depend on certain proteins being produced.
Making a protein involves ‘translating’ its sequence from template
molecules called messenger RNA (mRNA), which are ‘transcribed’ from the
gene that encodes the protein. During the low body temperatures experienced during
torpor, both of these processes stop. So how is the hibernator able to quickly and
efficiently heat itself up during the arousal periods of hibernation?
Grabek et al. investigated this by analyzing the relative levels of mRNA in the brown
adipose tissue of hibernating 13-lined ground squirrels. Using a special technique to
sample and sequence small fragments of mRNA taken from brown adipose tissue, Grabek
et al. compiled a profile of the mRNA molecules present at different points in the
torpor–arousal cycle and compared this with a similar profile taken from
squirrels that were not hibernating.
From this analysis, Grabek et al. detected that a particular group of mRNA molecules
that are required for producing heat increase in abundance during torpor, even though
body temperature is low enough to stop gene transcription. This increased abundance
does not occur because more of the mRNA molecules are made; instead, the mRNA
molecules are modified to become more stable and long lasting. Once the animal warms
up during arousal, gene transcription is reactivated and more new mRNA molecules are
Grabek et al. suggest that the key mRNAs required for brown adipose tissue function
are selectively stabilized during torpor through a temperature-dependent protective
mechanism. These mRNAs are then preferentially translated into proteins during
arousal to rapidly and efficiently heat the hibernator. Most other mRNA molecules
degrade throughout torpor, and so their numbers decline as replacements are not
transcribed until body temperature briefly recovers during arousal. Whether this
protective mechanism is also used in other tissues during torpor remains a question
for future work.