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The Hibernation Continuum: Physiological and Molecular Aspects of Metabolic Plasticity in Mammals

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Mammals are often considered to be masters of homeostasis, with the ability to maintain a constant internal milieu, despite marked changes in the environment; however, many species exhibit striking physiological and biochemical plasticity in the face of environmental fluctuations. Here, we review metabolic depression and body temperature fluctuation in mammals, with a focus on the extreme example of hibernation in small-bodied eutherian species. Careful exploitation of the phenotypic plasticity of mammals with metabolic flexibility may provide the key to unlocking the molecular secrets of orchestrating and surviving reversible metabolic depression in less plastic species, including humans. ©2015 Int. Union Physiol. Sci./Am. Physiol. Soc.
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The Hibernation Continuum:
Physiological and Molecular Aspects of
Metabolic Plasticity in Mammals
Mammals are often considered to be masters of homeostasis, with the ability
to maintain a constant internal milieu, despite marked changes in the envi-
ronment; however, many species exhibit striking physiological and biochem-
ical plasticity in the face of environmental fluctuations. Here, we review
metabolic depression and body temperature fluctuation in mammals, with a
focus on the extreme example of hibernation in small-bodied eutherian spe-
cies. Careful exploitation of the phenotypic plasticity of mammals with met-
abolic flexibility may provide the key to unlocking the molecular secrets of
orchestrating and surviving reversible metabolic depression in less plastic
species, including humans.
Frank van Breukelen,
1
and
Sandra L. Martin
2
1
School of Life Sciences, University of Nevada, Las Vegas,
Nevada; and
2
Department of Cell and Developmental Biology,
University of Colorado School of Medicine, Aurora, Colorado
sandy.martin@ucdenver.edu
Patterns of Heterothermy in
Mammals
In birds and mammals, endothermy is defined as
an increase of resting or routine oxygen consump-
tion that is 5- to 15-fold higher than that ob-
served in similar sized ectotherms (89). The result
of this increased metabolism is an increased body
temperature (T
b
). Conversely, decreased metabo-
lism is accompanied by reduced T
b
. Modification
of the thermoregulatory setpoint in mammals al-
lows for control of both T
b
and metabolism (29);
when the setpoint is lowered to approach an am-
bient temperature that is below T
b
, both metabo-
lism and T
b
decrease. Hibernation lies at the
extreme end of a broad spectrum of phenotypes in
endotherms that conserve energy by lowering me-
tabolism and hence T
b
(FIGURE 1).
Slow-wave sleep is considered the most shallow
form of metabolic depression and is common to all
mammals (4). T
b
is only slightly depressed
(FIGURE 2A), and oxygen consumption is reduced
just 10-15% in this state (95). Torpor is a deeper
form of metabolic depression that can be ex-
pressed in a variety of patterns. In daily torpor,
core T
b
is usually moderately depressed below
33°C for relatively short periods of time, e.g., 24 h
(FIGURE 2B). In the white-footed mouse, Peromys-
cus leucurus, effective daily torpor use can result in
an energetic savings of 74% (85). The most extreme
form of metabolic depression in mammals occurs
during deep hibernation (FIGURE 2C), as exempli-
fied by small-bodied, temperate-zone species from
a wide range of taxa (reviewed in Refs. 7, 70). In
some hibernators, oxygen consumption decreases
to as low as 1% of active rates and T
b
to as low as
2.9°C (2), leading to a seasonal energy savings of
as much as 90% (88). Historically, some authors
have used the term estivation to describe torpor
bouts that are longer than 1 day (characteristic of
hibernation) but occur in warm dry periods rather
than in the cold (93). As our knowledge of the
thermoregulatory and activity patterns of different
mammalian species increases (reviewed in Refs.
21, 22), so does our appreciation of the extent of
their metabolic flexibility.
At this point, it is important to attempt to dispel
some of the confusion surrounding the nomencla-
ture of hibernation and torpor. Some of this con-
fusion may be the result of the diversity of
metabolic strategies underlying torpor use and of
hibernation patterns. Most authors refer to torpor
as a physiologically controlled depression of met-
abolic rate and activity. Torpor initiates with a
regulated lowering of heart, respiratory, and met-
abolic rates as well as T
b
setpoint, which allows T
b
to approach ambient temperature (FIGURE 2, B
AND C). After a period of low metabolic activity
and stable, but lowered T
b
, the animal elevates
heart, respiratory, and metabolic rates to initiate
rewarming and restoration of active T
b
, recovering
from torpor (FIGURE 2B). Many species use torpor
to conserve energy during their daily periods of
inactivity; this pattern of torpor utilization is daily
torpor or daily heterothermy (FIGURE 2B). Here,
we will use the terms “daily torpor” and “daily
heterothermy” interchangeably. In contrast to the
pattern in daily heterotherms, torpor bouts in deep
hibernators have classically been defined as ex-
tending to longer than 1 day; these are typically
confined to the cold or dry season when food re-
sources become limiting. Given that hibernation
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was first described as “winterschlaf,” a widely use-
ful and historically correct definition of hiberna-
tion is “multiday bouts of torpor during winter.”
During deep hibernation, the multiday periods of
torpor are punctuated periodically by arousals to
euthermia, also known as interbout arousals, giv-
ing rise to a pattern of heterothermy (FIGURE 2C).
Unfortunately, the hibernation literature is often
confused by indiscriminate use of the word “hiber-
nation” to mean the period of low T
b
(e.g., torpor),
the entire season of heterothermy, or both. Here,
we define hibernation to be the season of torpor
utilization (FIGURE 2C) and will further specify the
physiologically distinct stages of hibernation,
which are minimally 1) entering; 2) maintaining, or
3) arousing from torpor; and 4) interbout euther-
mia (IBE; FIGURE 2D).
The physiological mechanisms controlling tem-
perature and metabolism during entry into and
exit from torpor, whether they occur in the pattern
context of daily torpor or hibernation, appear to be
identical (Ref. 93; compare FIGURE 2, B AND D). It
is important to note that, despite the shared fea-
ture of lowered T
b
between mammalian torpor and
hypothermia, the controlled lowering of T
b
set-
point and metabolism during torpor is unique to
torpor; in hypothermia, metabolic rate is elevated
as T
b
drops, such that a great deal of energy is
expended attempting to fight the decline in T
b
.
This is the exact opposite of what happens during
entrance into torpor. Additionally, the hypother-
mic mammal is unable to orchestrate a spontane-
ous recovery from low T
b
using endogenous
mechanisms (9), whereas the ability to rewarm
spontaneously is a key feature of natural torpor.
Much of our knowledge about the physiology of
torpor and patterns of torpor utilization in mam-
mals originates from work on rodents. Mice and
other murid rodents have been excellent models
for studies of daily torpor, whereas ground squir-
rels and other sciurid rodents have been widely
used for hibernation studies (12). As we will see,
many mammals deviate in various ways from the
classical patterns of hibernation seen in these
models and illustrated in FIGURE 2. For instance,
black bear hibernation (“denning”) consists of a
continuous torpor for months despite cyclical
warming (Ref. 76; FIGURE 3A). Oxygen consump-
tion during denning may be reduced to 25% of
basal values. These data suggest a metabolic
suppression independent of T
b
. However, other
indicators imply a more shallow torpor status than
that of ground squirrels. In bears, there is only a
moderate depression of T
b
to 30°C, and females
give birth and nurse their neonate(s) during the
denning period. Although often cited otherwise,
there are data to suggest depressed but sustained
kidney function and urine production in denning
bears, which is absent under normal conditions in
ground squirrels (e.g., Refs. 8, 31, 38, 60). In other
words, hibernation can be accompanied by mark-
edly varying physiological attributes depending on
species.
In attempting to designate hibernation vs. daily
torpor sensu stricto, it is important to consider the
evolutionary origins of torpor and endothermy.
The predominant view in the earlier literature as-
sumes torpor use evolved as a derived phenotypic
response to survive the hardships of a boreal win-
ter (50). These assumptions include consideration
of basal mammals as maintaining high and stable
T
b
. However, many mammals, including marsupi-
als, monotremes, and even some placental species
such as tenrecs, are considered protoendothermic
and demonstrate highly variable T
b
, even during
their active season (FIGURE 3B).
Tenrecs are Afrotherians and are related to ele-
phants, manatees, elephant shrews, and hyraxes.
Tenrecidae consists of some 10 genera encompass-
ing 35 species, with all but three of these being en-
demic to Madagascar (1, 20). There is tremendous
diversity among the tenrecs in niche, morphology,
and use of torpor. These protoendotherms may be
the closest extant representatives to a very early
mammalian ancestor (61). Genetic and morphologi-
cal studies of the evolution of placental mammals
have been unable to establish a robust phylogeny.
Significant support exists for at least three different
origins of placental mammals; in at least one of
these scenarios, Afrotherians are basal to the
other placental mammals (e.g., Exafroplacentalia
rooting; Ref. 68).
Several features of metabolic flexibility in mam-
mals blur the distinctions between daily torpor and
hibernation. Tenrecs highlight the difficulties in
strictly delineating daily torpor vs. hibernation. Al-
though much remains to be discovered regarding
tenrec hibernation and torpor use, the available
data suggest marked inter- and intra-species dif-
ferences in the extent and duration of torpor use.
In one study, investigators implanted temperature
loggers in penned lesser hedgehog tenrecs, Echi-
nops telfairi (49), and found the winter season con-
sists primarily of daily torpor bouts. However, one
individual experienced bouts of torpor that lasted
up to 4 days–a period most would consider char-
acteristic of hibernation. The data suggest these
extended torpor bouts are due to large fluctuations
FIGURE 1. A continuum of metabolic depression in
mammals
Energy consumption from least (dark blue, hibernation) to most
(no color, actively foraging). SWS, slow-wave sleep.
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in ambient temperature and that E. telfairi may be
changing its normal active period to exploit the
energetic advantages of passive rewarming. In
greater hedgehog tenrecs, Setifer setosus, hiberna-
tion consists of conforming largely to fluctuations
in ambient temperature that include temperatures
that exceed those experienced by the thermoregu-
lating animal in the active season (47, 51). In con-
trast to the rather modest hibernation pattern of E.
telfairi or S. setosus, the common or tailless tenrec,
Tenrec ecaudatus, undergoes deep hibernation.
Rather than choosing tree holes or shallow bur-
rows like E. telfairi or S. setosus,T. ecaudatus
hibernates underground (52). These animals expe-
rience low T
b
throughout their extended hiberna-
tion season, with no interbout arousal that
characterizes every other known deep hibernator
(52). We very recently acquired a colony of T. ecau-
datus and found that animals are consistently le-
thargic during the Austral winter even when
housed at 28°C or handled, although the depth of
this lethargy is variable (van Breukelen F, personal
observations). This contrasts to the end of the hi-
bernation season in ground squirrels, when ani-
mals spontaneously cease to orchestrate torpor
bouts and return to homeothermy, i.e., they main-
tain a narrowly regulated and stable T
b
(12, 80). On
the other hand, it is similar to what is seen in bears,
who, along with T. ecaudatus, end their hiberna-
tion season by gradual resumption of feeding and
increased activity over the course of a few weeks in
a state of “walking torpor.” More surprisingly is
that preliminary observations (van Breukelen F,
unpublished observations) suggest sporadic facul-
tative torpor or hibernation at ambient tempera-
tures from 11 to 28°C in individual tenrecs during
the active season, when their conspecifics are re-
producing, eating, and generally active.
As indicated earlier, daily torpor is generally
characterized by a modest depression of T
b
, i.e,
below 32°C (93). However, in another Afrotherian,
the rock elephant shrew, Elephantulus myurus,T
b
may become quite low (5–10°C) despite short tor-
por bout lengths that are 27 h (57). It would be
very easy and perhaps appropriate to ascribe the
Afrotherians as being atypical. However, patterns
of torpor use that defy ready assignment as either
daily torpor or hibernation can also be found in
phylogenetically distinct species such as lemurs.
Fat-tailed dwarf lemurs, Cheirogaleus medius, hi-
bernate in tree holes for extended periods (as
much as 7 mo) despite ambient temperatures
that may be over 30°C during the day (13, 14).
These lemurs experience an apparent poikilo-
thermy that is quite distinct from the more usual
poikilothermic behavior of ectotherms, because
the torpid dwarf lemur may periodically increase
its T
b
to above ambient temperature. Remarkably,
the dwarf lemur’s T
b
pattern depends on its tree
hole, i.e., the ambient temperature fluctations. If
the tree hole is poorly insulated and its tempera-
ture regularly exceeds 30°C, the animal appears to
be strictly poikilothermic, that is, T
b
closely tracks
the temperature of the tree hole (FIGURE 3C). If the
dwarf lemur spends too many consecutive days
below 30°C in a better-insulated tree hole, how-
ever, it periodically adds a boost of metabolic heat
production during the rewarming phase of the
daily ambient temperature cycle to drive T
b
to
above 30°C and above the temperature in the tree
hole (FIGURE 3D). Finally, if that same animal
moves to a very well insulated tree hole where the
ambient temperature remains more constant and
close to 20°C, the lemur’s T
b
rhythm looks much
more like hibernation in a temperate-zone mam-
mal, with continuous torpor at low T
b
punctuated
FIGURE 2. Schematics illustrating rhythms of sleep, daily tor-
por, and deep hibernation
A: 8 days in summer, golden-mantled ground squirrel (Martin SL, un-
published observations). B: daily torpor in Glis glis showing body tem-
perature (T
b
), ambient temperature, and metabolic rate (data adapted
from Ref. 93). C: ground squirrel hibernation: T
b
across 8 mo illustrates
the homeothermic and heterothermic (blue shadow) periods (T
b
trace is
adapted from Ref. 3). D: metabolic rate and T
b
during various hiberna-
tion phases in Glis glis. IBE, interbout euthermia. Data are adapted from
Ref. 93. In all panels, blue lines represent body temperature, red lines
represent metabolic rate, and dashed black lines represent ambient
temperature.
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PHYSIOLOGY • Volume 30 • July 2015 • www.physiologyonline.org 275
by short arousals to euthermia (FIGURE 3E) that
are driven by a large increase in metabolic rate
(15). During the dry season in mouse lemurs, Mi-
crocebus griseorufus, there are marked inter-indi-
vidual variations in torpor use that may extend
from daily torpor to hibernation over the course of
weeks (43, 44). Other mammals, including the mar-
supial Smithopsis macroura, also avail themselves
of passive solar warming in their torpor ecology
(53).
It has been argued that daily torpor and hiber-
nation are discrete adaptations (70) rather than
belong to a continuum (7) of metabolic plasticity,
as illustrated in FIGURE 1. We note that the plas-
ticity within individuals to orchestrate diverse pat-
terns of metabolic activity and T
b
, as seen with
dwarf lemurs moving among different tree holes
with different insulating properties (FIGURE 3,
C–E; Ref. 14); dormice engaging in daily torpor,
hibernation, and estivation (93); highly variable T
b
patterns of ground squirrels preparing for hiberna-
tion during fall (71); seasonal changes in torpor
bout duration and frequency of arousal that leads
to reproducibly longer periods of torpor mid-hi-
bernation season (23); and variable patterns of
woodchuck hibernation depending on environ-
mental conditions (97); taken together with the
intermediate torpor utilization patterns of the
Patagonian opossum (24) and tenrecs described
above are consistent with the view that the meta-
bolic plasticity observed among mammals repre-
sents a continuum of possible phenotypes rather
than fixed discrete patterns. It is reasonable to
infer that the apparent clustering of features, such
as minimum T
b
and metabolic rate during torpor
or maximum torpor bout length, into apparently
distinct pattern groups for daily torpor and hiber-
nation (70) may reflect optimal conditions for en-
ergy conservation given specific conditions of
ambient temperature and body size taken together
with strategies for avoiding predation and enhanc-
ing reproduction (79, 96).
The Mysterious Periodic Arousals
from Torpor That Give Rise to
Heterothermy in Hibernators: Or,
Why Arouse?
With the exception of the common tenrec de-
scribed above, all deep hibernators, e.g., animals
spending multiple days with low T
b
, experience
periodic arousals to euthermia between bouts of
torpor (IBE; FIGURE 2; Refs. 12, 52). These periodic
arousals are paradoxical because hibernation is
reasonably presumed to be an energy-saving ad-
aptation, yet at least 70% of the energy consumed
over a ground squirrel’s hibernation season is used
to drive the periodic arousals from torpor (88).
Given that so much more energy could be saved by
remaining torpid continuously, why would an
animal apparently waste it to repeatedly restore
high T
b
numerous times over a period of many
months? The answer to this question remains one
Temperature (C˚) Temperature (C˚)
10
1023
Time (days)
Time (days)
45
15
20
25
30
35
-40
1 16 31 15 30 1 16 31 15 30
-20
0
34
36
38
30
32
A
B
Temperature (C˚)
0
10
20
30
40
0
10
20
30
40
0
10
20
30
40
C
D
E
FIGURE 3. Variation in patterns of heterothermy in mammals
A: hibernation in black bear over 5 mo. Figure is modified from Ref. 76 and used with permission. B: Tenrec body temperature flexibility and
ambient temperature over 5 days (van Breukelen F, unpublished observations). C–E: dwarf lemurs in different tree holes, from least (C) to most
(E) insulated, based on ambient temperature difference from outside to tree-hole, as described in Ref. 14. All panels, blue represents T
b
, and
dashed black represents T
a
.InA, red tics show movement; in C-E, red lines show outside T
a
vs. treehole T
a
in black.
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of hibernation’s biggest mysteries, despite sub-
stantial speculation and research effort.
There is no question that, as a hibernator recov-
ers from the near-freezing temperatures of torpor,
the activities of cell and molecular processes that
slowed at low T
b
(the so-called Q
10
effect) are rap-
idly elevated throughout the body, along with the
more apparent physiological processes. But is this
biochemical activation effectively equivalent to
halting a reaction on ice and restarting it by mov-
ing it to 37°C (temperature explains both cause and
effect), or is arousal actually triggered by the need
to restore one or more of those processes, and, if
so, which process is key? In most cases where a
given process has been claimed as the reason un-
derlying the periodic arousals, it is more likely that
the process simply resumed because T
b
was re-
stored; among these are DNA, RNA and protein
synthesis, cell division, various aspects of immune
function, and sleep (reviewed in Refs. 12, 80). More
recent findings of alterations that occur during tor-
por and are restored during the interbout euther-
mic periods include dendritic retraction (69, 86,
87), leukocyte sequestration in secondary lym-
phoid organs (6), receptor-mediated endocytosis
(39), protein degradation in the proteasome (83),
and IRES-dependent initiation of translation (63).
It has been argued for decades that the hiberna-
tor’s periodic arousals from torpor are needed to
rectify some imbalance that accrues at low T
b
(FIGURE 4; reviewed in Ref. 54). This view is sup-
ported by the strong association of torpor bout
length with total metabolism. Specifically, elevated
oxygen consumption rates during torpor occur ei-
ther when T
b
is elevated due to higher ambient
temperature or when hibernators increase meta-
bolic heat production to maintain a near (but
above) freezing T
b
against ambient temperatures
that are well below freezing (10). In both cases,
torpor bout lengths are shortened, thereby tying
torpor bout duration to overall metabolism. These
data are consistent with at least two possible
mechanisms: 1) depletion or accrual of a metabolic
product that causes arousal from torpor
(FIGURE 4)or2) a lengthening of the normal cir-
cadian clock leads to a more extreme version of the
standard mammalian daily activity cycle (54). In-
terestingly, these two seemingly disparate views
may actually not be separable, since there is grow-
ing appreciation for the impact of metabolites and
metabolism on the transcription/translation feed-
back loops that orchestrate the mammalian circa-
dian system (16, 46, 64, 66).
If the circadian system is merely extended to
specify a torpor-arousal cycle, it predicts that tor-
por bout length is related to a central nervous
system-based timer. As depicted in FIGURE 1, daily
torpor and hibernation can be considered elabo-
rations of mechanisms evoked for slow-wave sleep
(30), a view supported by the marked similarities
FIGURE 4. Kinetic model of biochemical alterations determining torpor-arousal cycles
A: a hypothetical critical inducer/enabler of torpor (blue) increases during the euthermic period and then slowly depletes over the
torpor bout. B: conversely, an inhibitor of torpor (or activator of arousal, red) accumulates at low T
b
during torpor and is eliminated
during the euthermic arousal (IBE). Although definitive evidence for either an inducer or an inhibitor of torpor is lacking, there are
circulating metabolites that have been shown to cycle as predicted in both Aand B. Several amino acids, modified amino acids, ace-
toacetate, and degradation products of branched-chain amino acids deplete during torpor but are restored during each IBE (A)in
hibernating ground squirrels. Conversely, other modified and unmodified amino acids, vitamin B metabolites, myo-inositol, and allan-
toin accumulate across the torpor bout and are restored to lower levels (B) before entrance into the next bout of torpor (17). Clearly
frequent, precisely timed samples are needed to capture these types of abundance changes over the torpor-arousal cycle; metabolite
and gene product dynamics will be obscured by averaging among randomly collected torpor vs. IBE samples.
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between sleep and torpor physiology, e.g., reduced
T
b
setpoint, lowered electroencephalographic ac-
tivity, and behavioral quiescence. Sleep timing and
duration are greatly influenced by circadian
rhythm function (11); thus it is plausible that the
simplest path to evolving a timer for hibernation
cycles is via adaptation of the circadian timer. The
view that periodic arousals during hibernation are
the result of a lengthened circadian activity-inac-
tivity cycle was proposed long ago (54) and has
since been elaborated (55). In effect, given an os-
cillator that is not temperature compensated, tor-
por bouts of hibernation can be considered 1 long
circadian day (or night) at the molecular level. This
view has significant merit. The canonical view of
the mammalian molecular clock consists of tran-
scription factors CLOCK and BMAL1 driving the
transcription of cryptochrome and period (per)
genes, which then feedback to inhibit clock and
bmal1 gene expression (42). Oscillations are de-
pendent on transcription, translation, and mRNA
and protein degradation; processes we know are
markedly depressed during torpor in hibernating
ground squirrels (81–83) and hamsters (62), and
less, but nevertheless significantly, depressed in
Djungarian hamsters torpid at 25°C during daily
heterothermy (5).
In hibernating European hamsters, in situ hy-
bridization of the superchiasmatic nucleus shows
that per1,per2, and Bmal1 cease to cycle in a
circadian manner across torpor bouts (65). Fur-
thermore, the mRNA hybridization intensity for
arylalkylamine N-acetyltransferase, the clock-re-
sponsive gene that controls melatonin synthesis
in the pineal gland, as well as that of arginine
vasopressin are consistent with torpor being a
prolonged, continuous night phase. Unfortunately,
the sampling frequency in this study was insuffi-
cient to determine whether the clock is simply
slowed in torpor-arousal cycles or whether it is
completely abandoned. However, gene expression
changes measured by quantitative methods on
RNA extracts from hibernating ground squirrels
indicate that a peak of circadian gene expression
occurs in the hypothalamus and in peripheral tis-
sues during the euthermic arousals (73, 94), con-
sistent with a possible role for this system in the
timing of torpor-arousal cycles during hibernation.
In contrast to these limited molecular data, how-
ever, results from careful field studies on male
arctic ground squirrels seem to favor the view that
the circadian system ceases to function during hi-
bernation. Body temperature was continuously el-
evated but was arrhythmic for as many as 10–27
days while the animals remained sequestered in
their hibernacula before spring emergence and ex-
posure to light. Interestingly, these same males
retained a free-running circadian rhythm in similar
conditions after immergence into their hibernacula
in the fall but before the onset of heterothermy (90
92). A more inclusive and precisely timed sampling
strategy for assessment of the molecular circuitry of
the circadian system during torpor-arousal cycles is
needed to determine conclusively whether the clock
simply stops ticking during hibernation or whether it
continues with normal, albeit slowed, rhythm.
Just as deciphering the molecular components of
the circadian system requires precisely timed, fre-
quent sampling (37, 45, 48, 67), so will deciphering
the molecular components of hibernation. And,
like the circadian circuitry (42), hibernation cir-
cuitry is no doubt complex, with multiple levels of
regulation; it clearly involves distinct gene expres-
sion responses in different organ systems through-
out the body (18, 19, 25–28, 32–35, 39, 56, 73, 84,
94), which may be controlled by underlying meta-
bolic status (17, 40, 64, 66, 72, 75, 77, 78). It is
reasonable to hypothesize that interactions be-
tween changing metabolite concentrations and the
core clock components lead to torpor-arousal cy-
cles. Arousal could be caused by either depletion of
a factor (or factors) critical for torpor (FIGURE 4A)
or accumulation of a factor(s) inhibitory for torpor
(FIGURE 4B). There is growing evidence for accu-
mulation or depletion of certain plasma (17, 58) or
liver (59, 74) metabolites during torpor. However,
studies of hibernators to date have lacked the sam-
pling precision, intensity, or depth to elucidate the
key players. From FIGURE 4, it is clear that impre-
cise sampling will erase all chance of finding mol-
ecules with the expected kinetics of key molecular
components of the cycle. The complexity of hiber-
nation is further increased by the fact that more
than one cycle may be involved, with a seasonal
FIGURE 5. Torpor-arousal cycles
in ground squirrels are embed-
ded in a seasonal cycle
The circannual rhythm of hibernation
is represented by the outer circle (ho-
meothermic period in red; hetero-
thermic, i.e., hibernation in blue), and
the torpor-arousal cycle is repre-
sented by the inner circle (IBE, green;
torpor, dark blue).
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PHYSIOLOGY • Volume 30 • July 2015 • www.physiologyonline.org278
cycle superimposed on the torpor-arousal cycle
(FIGURE 5); key factors, e.g., the nutritional and
reproductive status of the animal, vary tremen-
dously across the season (12). Therefore, the tim-
ing of sample collection across the year is also
crucial for molecular studies involving hibernators.
The importance of the seasonal framework is high-
lighted by results of a recent study showing that
muscle atrophy precedes rebuilding in hibernating
13-lined ground squirrels (36) and the finding that
a seasonal change in purinergic signaling confers
sensitivity to induction of torpor by an adenosine
receptor agonist in Arctic ground squirrels in
winter (41).
The use of a multi-species comparative ap-
proach may also facilitate elucidation of torpor
timing mechanisms. In ground squirrels, there are
pronounced cycles of torpor and arousal that im-
ply a robust timing system. In common tenrecs
and bears, animals remain torpid for the entire
season. In dwarf lemurs, the animals must appar-
ently reach a T
b
of 30°C to maintain torpor, oth-
erwise, they arouse. When married to an
elucidated molecular model of timing, the diversity
represented in these species could provide the
means to resolve one of hibernation’s greatest
mysteries: Why arouse? Despite much speculation
to the contrary, biochemical mechanisms that de-
termine the torpor-arousal cycle are not well un-
derstood. We believe that revealing these
mechanisms will be the key to engineering safe,
reversible metabolic depression in humans for a
wide range of applications, and hence such under-
standing deserves vigorous pursuit.
No conflicts of interest, financial or otherwise, are de-
clared by the author(s).
Author contributions: F.v.B. and S.L.M. analyzed data;
F.v.B. and S.L.M. interpreted results of experiments; F.v.B.
and S.L.M. prepared figures; F.v.B. and S.L.M. drafted
manuscript; F.v.B. and S.L.M. edited and revised manu-
script; F.v.B. and S.L.M. approved final version of
manuscript.
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... It has been argued, on the other hand, that the simplest path to evolving a timer for hibernation cycles is via adaptation of an existing timing mechanism, the circadian system (van Breukelen and Martin, 2015). This led to the view mentioned above that a torpor/arousal cycle is considered a single non-temperature compensated circadian day (Malan 2010;(van Breukelen and Martin, 2015). ...
... It has been argued, on the other hand, that the simplest path to evolving a timer for hibernation cycles is via adaptation of an existing timing mechanism, the circadian system (van Breukelen and Martin, 2015). This led to the view mentioned above that a torpor/arousal cycle is considered a single non-temperature compensated circadian day (Malan 2010;(van Breukelen and Martin, 2015). ...
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... However, subsequent, comprehensive comparisons showed only an extremely weak dependency of torpor metabolic rate on body mass among hibernating mammals (Ruf and Geiser, 2015). Also, if each torpor episode represented a single circadian cycle (Malan, 2010;van Breukelen and Martin, 2015), this would require a nontemperature compensated clock, which contradicts the empirical evidence (Rawson, 1960;Zimmerman et al., 1968). Moreover, in free-living dormice, for example, a single circadian day would have to be lengthened from 24 h to >800 h during midwinter (Hoelzl et al., 2015). ...
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... Much of the relatively recent work on the metabolic torpor spectrum has focused on mammals (Boyles et al., 2020;Kräuchi and Deboer, 2011;Reher and Dausmann, 2021;Ruf and Geiser, 2015;van Breukelen and Martin, 2015). Energetic, neurological (electroencephalogram, EEG), transcriptomic and ecological evidence exists for a physiological continuum from shallow to deep torpor in mammals, as found in several ground squirrel species, marmots and kangaroo rats (Berger, 1984;Canale et al., 2012;Florant and Heller, 1977;Glotzbach and Heller, 1976;Heller, 1979Heller, , 1978Walker et al., 1977Walker et al., , 1979. ...
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AimThe ability of endotherms to physiologically regulate body temperature (Tb) is presumed to be important in the adaptive radiation of birds and mammals. Recently, attention has shifted towards determining the extent and energetic significance of Tb variation documented in an ever-expanding list of species. Thus, we provide the first global synthesis of ecological and evolutionary correlates of variation in mammalian Tb. LocationWorld-wide Methods We conducted a phylogenetically informed analysis of Tb variation using two complementary metrics, namely Thermoregulatory Scope (TS) and Heterothermy Index (HI), that treat Tb variation as a continuous variable. We included morphological (e.g. body mass), ecological (e.g. food habits) and environmental (e.g. latitude) correlates in the analysis. ResultsAmong 560 mammal species included in the TS analysis, Tb relates most strongly to body mass (included in all models), season (relative parameter weight: 0.95), absolute latitude (0.80) and hoarding behavior (0.72), with small-bodied, high latitude and non-hoarding species expressing the most Tb variation. Small-bodied and high latitude species also express a greater range of thermoregulatory patterns than large-bodied and low latitude species. Results were generally similar in HI analysis, but in summer the extent of heterothermy decreases with latitude. Main conclusionsMammalian heterothermy is related to evolutionary history, climate conditions constraining minimum Tb, resource conditions mediating energy supply for maintaining high Tb, and latitudinal variation in the nature of seasonality. Our analysis further shows that traditional classification of mammals as hibernators, daily heterotherms or homeotherms is clouded or possibly misleading.