Metabolism of normothermic woodchucks during prolonged fasting
Biology Department, University of Ottawa, Ontario, Canada
Author for correspondence (e-mail:
jmweber{at}science.uottawa.ca)
Accepted 27 September 2004
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Summary |
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Key words: metabolic depression, fuel selection, lipids, protein sparing, metabolic rate, oxygen consumption, energy expenditure, food deprivation, woodchuck, Marmota monax, rabbit
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Introduction |
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Hibernators are among the mammalian champions of long-term fasting and a
lot of information is available on their metabolism during hypothermia
(Wang and Lee, 1996). Much
less is known about oxidative fuel selection during normothermia, even though
many hibernators continue to rely on their endogenous energy reserves long
after coming out of hibernation. For example, woodchucks Marmota
monax (Davis, 1967
;
Hamilton, 1934
;
Snyder et al., 1961
) and
American black bears Ursus americanus
(Nelson, 1980
) are known to
continue fasting for several weeks after spring arousal, even though snow has
melted and food is readily available. Numerous studies have investigated the
biology of hibernators (for a review, see
Humphries et al., 2003
), but
no information is available on their response to fasting under normothermic
conditions. They show seasonal changes in energy expenditure, with lower
normothermic metabolic rates during the fall, and as much as a 96% decrease
during actual hibernation (Körtner
and Heldmaier, 1995
). However, it is not known whether they use
metabolic depression during prolonged normothermic fasting, a strategy
commonly observed in non-hibernators
(Choshniak et al., 1995
;
Keys et al., 1950
;
Ma and Foster, 1986
;
Merkt and Taylor, 1994
).
Depressing metabolism under normothermic conditions could be a very valuable
compromise to delay the depletion of energy reserves without the loss of
alertness and mobility imposed by hibernation. In this study, our goal was to
quantify the metabolic response of normothermic woodchucks to prolonged
fasting. We used indirect calorimetry and nitrogen excretion analysis to
determine: (1) the presence and/or extent of metabolic depression, (2) the
pattern of changes in oxidative fuel selection and nitrogenous waste
production, and (3) whether these metabolic responses show seasonal
differences by comparing animals in early spring and in summer. As a
reference, we also carried out parallel experiments under identical
conditions, but on New Zealand white rabbits, a species of similar size and
diet as the woodchuck, but not adapted for prolonged fasting.
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Materials and methods |
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Fasting protocols
Food was provided for the first 3 days of each experiment while food
consumption rate was monitored to obtain baseline values. Then, the animals
were fasted for the remainder of the measurements. Water was available ad
libitum at all times. All experiments were approved by the Animal Care
Committee of the University of Ottawa that imposed maximal values for fasting
duration and weight loss in each species. For the rabbits, the experiments had
to be terminated after a maximum of 7 days without food, or when they had lost
15% of initial body mass. For the woodchucks, fasting was allowed for up to 14
days, or until they had lost 30% of initial body mass.
Measurements of gas exchange and nitrogen excretion
Animals were measured individually in a closed Plexiglas respirometer (54
cmx38 cmx67 cm) supplied with room air at 3-8 l min-1.
Rates of O2 consumption and CO2 production were measured
in a respirometer (Oxymax system, Columbus Instruments, Columbus, Ohio, USA)
as described previously (Fournier and
Weber, 1994). Gas exchange measurements were interrupted for
30 min once a day to weigh the animals, measure rectal temperature, clean
the respirometer, and calibrate the analyzers. The respirometer floor was
modified to allow the collection of urine in a vessel containing a thymol
crystal and placed on ice to prevent bacterial growth. The volume of urine
produced was measured every 24 h and a daily subsample was frozen to measure
total nitrogen and the main nitrogenous waste products: ammonia, urea, uric
acid and creatinine.
Body composition
Additional animals of the same batch (2 spring woodchucks, 2 summer
woodchucks and 3 rabbits) were euthanized by overdose of pentobarbital in the
post-absorptive state (12 h after their last meal) to determine body
composition before fasting. Skeletal muscle, adipose tissue, liver and heart
mass were measured after careful dissection.
Analyses and calculations
Total urinary nitrogen was measured using the Kjeldahl method (Tecator
analyzers, 1007 Digester and Kjeltec System 1002 Distilling Unit, Hoganas,
Sweden). The concentrations of individual nitrogenous compounds of urine were
quantified spectrophotometrically. Urea was determined using the
urease/glutamate dehydrogenase method and uric acid was measured using the
uricase method (Bergmeyer,
1985). Creatinine was measured using a commercial kit (Sigma
diagnostics kit, St Louis, MO, USA). Total ammonia
(NH3+NH4+) was measured according to the
method of Verdouw (1978
).
Protein oxidation (in g) was calculated by multiplying total urinary nitrogen
excretion (in g) by 6.25, assuming that the proteins oxidized contained an
average of 16% N by weight. Rates of carbohydrate and lipid oxidation were
calculated according to the equations of Frayn
(1983
) as follows:
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Statistics
The effects of fasting were assessed by repeated-measures analysis of
variance (ANOVA) with time, individual animal and season or species as main
factors. When significant temporal changes were detected, the Dunnett's
post-hoc test was used to determine which fasting means were
different from control values from fed animals. Percentages were transformed
to the arcsine of their square root before statistical analyses. All values
are presented as means ± S.E.M. and significant differences
are indicated when P<0.05.
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Results |
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The relative contributions of the different metabolic fuels to total energy expenditure are presented in Fig. 4. Before fasting, the percentage contribution of lipid and carbohydrate oxidation was the same between spring and summer woodchucks (P>0.05), whereas protein oxidation was higher in the summer than in the spring (P<0.05; Fig. 4A). Lipids rapidly became the dominant fuel when fasting was initiated (Fig. 4B) and remained so until the end of the experiments (Fig. 4C). The seasonal difference in protein metabolism observed in the fed woodchucks disappeared during fasting because food deprivation decreased protein oxidation in the summer animals.
|
Differences between woodchucks and rabbits
No seasonal differences in body mass, metabolic rate, food consumption or
body temperature were observed in the rabbits (P>0.05) and,
therefore, spring and summer results were pooled for this species. A large
difference in oxygen consumption was observed between species. Both summer and
spring woodchucks had lower mass-specific metabolic rates than the rabbits
(P<0.05; Table 1). The summer woodchucks consumed as much food as the rabbits
(P>0.05), but their average body temperature was lower
(P<0.05) (Table
1).
During fasting, the rabbits lost weight more rapidly than the woodchucks (P<0.05; Fig. 1A). On the first day of fasting, the rabbits lost 34.4±5.0 g kg-1 day-1 compared to 17.3±1.7 g kg-1 day-1 for the woodchucks. However, the rate of weight loss of the rabbits decreased over time to reach 16.3±5.5 g kg-1 day-1 by the end of the fasting period (P<0.05; Fig. 1B). Regardless of this decrease, the rabbit experiments had to be interrupted after 7 days of fasting because they had already lost 15% of their body mass, compared to only 8% for the woodchucks (Fig. 1A). There was a very large difference in adipose tissue size between the 2 species. Carcass analysis of fed animals showed that the woodchucks had 2-4 times more fat than the rabbits relative to total body mass (P<0.05; Table 2).
The rate of oxygen consumption of the rabbits decreased sharply during fasting (P<0.05; Fig. 2). It showed a 32% reduction over 1 week without food, decreasing from 383±11 to 259±25 µmol O2 kg-1 min-1. This change in metabolic rate was correlated with a small decrease in body temperature (Pearson correlation coefficient=0.786; P<0.05). Mean body temperature was reduced from 39.3±0.3°C in the fed state to 38.4±0.1°C after 7 days of fasting (P<0.05; Fig. 3).
In fed animals, the contributions of lipid and carbohydrate oxidation to total oxygen consumption did not differ between woodchucks and rabbits, but protein oxidation was higher in the rabbits (P<0.05; Fig. 4A). This species difference in fuel utilization persisted during fasting (P<0.05; Fig. 4), even though food deprivation caused the rabbits to reduce protein oxidation (P<0.05; Fig. 4) and urinary nitrogen excretion (P<0.05; Fig. 5A).
|
Urinary nitrogen excretion
Total urinary nitrogen excretion of fed rabbits was 27.37±2.69
µmol N kg-1 min-1 compared to 12.26± 2.13
µmol N kg-1 min-1 for the summer woodchucks and
3.61±1.54 µmol N kg-1 min-1 for the spring
woodchucks (P<0.05; Fig.
5A). Rabbit nitrogen excretion decreased to 8.93±1.15
µmol kg-1 min-1 (P<0.05;
Fig. 5A) during the 7-day fast
(a 67% change). Total urinary N excretion of the summer woodchucks decreased
during the first 2 days of fasting to reach the low levels found in spring
woodchucks (Fig. 5A). The %
composition of individual nitrogenous compounds relative to total N excretion
did not differ between seasons in the woodchucks and, therefore, spring and
summer data were pooled (Fig.
5B-E). However, differences did exist between species. The
contribution of uric acid to total urinary N content was higher in rabbits
than in woodchucks, both before and during the fast (P<0.05;
Fig. 5E). Conversely, the
contribution of ammonia to total N content was higher in woodchucks than in
rabbits, before and during the fast (P<0.05;
Fig. 5C). The % contributions
of urea and creatinine to total N excretion were not different between species
(Fig. 5B,D). As total nitrogen
excretion decreased with fasting (Fig.
5A), so did the percentage contribution of urea after seven days
of fasting (P<0.05; Fig.
5B) (-22% for the woodchucks and -10% for the rabbits). The
contribution of ammonia to total N excretion of the woodchucks doubled during
the fasting period (P<0.05;
Fig. 5C). A similar increase
did not occur in the rabbits, where the contribution of ammonia to total
urinary nitrogen content remained around 1% throughout the fasting period.
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Discussion |
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Fasting-induced metabolic depression
In the fed state, metabolic rate is much higher in the summer than in the
spring (+35%; see Table 1), and
this observation is consistent with published measurements on post-absorptive
woodchucks and marmots (Bailey,
1965; Körtner and
Heldmaier, 1995
; Rawson et
al., 1998
). After spring arousal, a low basal metabolic rate
appears critical for surviving the normothermic fasting period that typically
follows 5 months of hibernation (Davis,
1967
; Hamilton,
1934
; Snyder et al.,
1961
). During fasting, metabolic depression was only used in the
summer (25% reduction in
O2 over 2 weeks;
Fig. 2), and it did not occur
in the spring. This observation suggests the interesting possibility that
normothermic, basal metabolism has a lower limit. The potential existence of a
minimum basal metabolic rate for normothermic mammals is supported by the fact
that summer and spring woodchucks reach the same rate of energy expenditure
after 14 days of fasting, even though their pre-fasting rates are very
different. Measurements on rabbits provide additional support for the same
concept because this species starts with a much higher post-absorptive
metabolic rate than spring or summer woodchucks, but it shows stronger
metabolic depression during fasting (-32% in only 7 days). The rapid decrease
in energy expenditure shown by rabbits is insufficient to completely offset
their high post-absorptive metabolic rate
(Table 1,
Fig. 2A), and, therefore, loss
of body mass is much more rapid in rabbits (-15% in 7 days) than in woodchucks
(-13% in 14 days) (Fig. 1). For
this reason, the rabbit experiments had to be terminated after 1 week
(according to the limit set by our animal care committee), and we could not
determine whether a longer period of fasting would eventually decrease the
metabolic rate of rabbits to the lower levels observed in woodchucks. In both
species, metabolic depression was accompanied by a small, but significant
decrease in body temperature (Fig.
3), as previously observed in other species including the rat
(Ma and Foster, 1986
). Like
spring woodchucks, other mammals with naturally low basal metabolic rates seem
to lack the capacity for metabolic depression during fasting. Experiments on
the Virginia opossum Didelphis virginiana, a marsupial of similar
body size (3-4 kg), revealed that this nocturnal species reaches its lowest
metabolic rate of
200 µmol O2 kg-1
min-1 (or 4.5 ml O2 kg-1 min-1)
during daylight sleep (see fig. 1 in Weber
and O'Connor, 2000
). This minimum post-absorptive rate is
identical to the lowest value observed here in woodchucks
(Fig. 2A) and the Virginia
opossum is not able to decrease its metabolic rate further in response to
fasting (Weber and O'Connor,
2000
).
The two main ATP-consuming processes accounting for basal metabolic rate
are trans-membrane ion pumping and protein synthesis
(Rolfe and Brown, 1997). It is
conceivable that mammals can only downregulate these essential processes to a
minimal level, below which normothermic life is compromised. For example,
decreasing the cost of ion pumping can be achieved by lowering ion leakiness
of membranes through changes in the degree of saturation of phospholipids
(Hulbert and Else, 2000
).
However, modifying phospholipid saturation will also affect many other
important membrane functions through changes in overall fluidity (e.g. insulin
sensitivity), and such widespread disruption may not be compatible with
mammalian life at
37°C. Another way to decrease energy expenditure
during fasting would be to lower mitochondrial proton leak, a process that
uncouples oxygen consumption from ADP phosphorylation. Two recent studies show
that fasting and calorie restriction do not affect proton leak
(Bézaire et al., 2001
;
Ramsay et al., 2004
), whereas
another suggests that proton leak is decreased via complex mechanisms
that vary with the duration of calorie restriction
(Bevilacqua et al., 2004
).
Clearly, the potential existence of a minimum normothermic metabolic rate in
endotherms, and the mechanistic limitations for its specific set point,
warrant further investigation.
Changes in fuel selection: protein sparing
In addition to metabolic depression, prolonged fasting has important
effects on fuel selection. In our experiments, the major changes elicited by
food deprivation took place within 2 days, and, therefore, all the values
measured after this time were pooled for each group of animals
(Fig. 4). In both species, the
dominant use of carbohydrates that normally support energy metabolism in the
post-absorptive state (phase I) was rapidly replaced by high lipid use (phase
II) as fasting was continued (Fig.
4). However, the most striking differences in fuel selection were
observed in relation to protein sparing. In the spring, woodchucks had the
lowest rate of net protein oxidation, presumably because their fuel selection
pattern reflected the hibernation state more closely than in the summer. In
the fed state, proteins only accounted for 8% of metabolic rate in spring
woodchucks, whereas it reached 17%
O2 in summer
woodchucks, and a high value of 28%
O2 in rabbits
(Fig. 4A). All groups had the
ability to decrease absolute and relative rates of net protein oxidation in
response to fasting. After more than 3 days without food, the contribution of
proteins was reduced to 5%
O2 in spring
woodchucks, 6%
O2 in summer
woodchucks and 20%
O2 in rabbits.
Therefore, woodchucks show a superior ability for protein sparing (also
reflected by much lower rates of water consumption and urine production than
the rabbits; see Fig. 6),
particularly during the summer. At this time of year, they can not only
decrease their overall rate of energy expenditure to cope with fasting, but
also dramatically reduce their reliance on proteins. This metabolic strategy
helps to conserve muscle mass and it has been observed in other species
adapted for prolonged fasting. Breeding adult seals and post-weaning seal pups
commonly cope for several weeks without food by reducing their metabolic rate
to
45% of normal values in fed animals and their reliance on proteins
down to 6% of
O2
(Nørdoy et al., 1993
,
1990
;
Worthy and Lavigne, 1987
).
However, the most extreme capacity for protein sparing may be found in bears.
During the summer, pack ice recession prevents polar bears U.
maritimus from hunting seals and they appear to lower protein oxidation
to 1% of
O2 in
response to fasting (Atkinson et al.,
1996
; Nelson,
1987
). Black bears Ursus americanus and grizzly bears
U. arctos decrease body temperature by a few degrees and metabolic
rate by
30% during their `pseudo-hibernation', which can last for up to 6
months (Watts et al., 1981
).
During this time, no nitrogen wastes are excreted
(Barboza et al., 1997
; Nelson,
1973
,
1980
;
Nelson et al., 1973
) and two
possible mechanisms have been invoked to explain this observation: (1) a
complete inhibition of protein oxidation and/or (2) the recycling of nitrogen
waste products. More recent experiments where muscle biopsies have been
sampled at the beginning and at the end of winter show that protein breakdown
of hibernating bears is actually significant but low
(Tinker et al., 1998
).
Therefore, they do have the ability to recycle nitrogen because no waste
products are accumulated during hibernation.
|
The exact pathways for nitrogen recycling have not been investigated in
detail, but urea hydrolysis may be the most important mechanism used by
woodchucks. To some extent, all mammals seem to be able to reabsorb urea
through the bladder, and to bring it to their digestive system where it can
undergo bacterial hydrolysis. The ammonia produced can then be recycled, and
this process has been demonstrated in several mammals
(Campbell and MacArthur, 1997;
Harlow, 1987
;
Singer, 2002
). The large
difference in nitrogen excretion between the two species examined here may be
explained by the fact that urea hydrolysis is particularly active in
woodchucks compared to rabbits. This hypothesis is consistent with the
observations that woodchucks produce very small volumes of urine
(Fig. 6B) (thus favoring urea
reabsorption through the bladder), and have a very large caecum (where
extensive bacterial fermentation can take place). Surprisingly, however,
metabolic tracer measurements have revealed that a closely related species
(the marmot: Marmota flaviventris) strongly reduces its rate of urea
hydrolysis during fasting (Harlow,
1987
). Identifying the exact pathways and quantifying their flux
in bears and true hibernators like woodchucks during normothermic fasting or
hibernation are exciting avenues for future research.
Apart from fueling energy metabolism, protein breakdown can also play an
important role in providing amino acids as a substrate for gluconeogenesis
(Peroni et al., 1997). Liver
glycogen is essentially depleted during phase I of fasting and glucose
production becomes dependent on gluconeogenesis during phase II
(Goodman et al., 1990
;
Nilsson and Hultman, 1973
). In
rats and humans for example, amino acids account for
25% of total
gluconeogenic flux during phase II (Owen
et al., 1998
), a contribution matching that of glycerol, an
end-product of lipolysis.
Nitrogen excretion
The nitrogenous waste products of amino acid oxidation are excreted in
urine as ammonia, urea and uric acid. Our analysis of changes in the relative
composition of nitrogen wastes reveals another energy-saving mechanism
associated with normothermic fasting in the woodchuck: a gradual shift away
from urea excretion accompanied by an increase in ammonia excretion
(Fig. 5). This change in
ammonia excretion may be related to an increase in urea hydrolysis.
Alternately, it could reflect a metabolic strategy aiming at decreasing the
energy cost of nitrogen waste disposal in woodchucks. Interestingly, rabbits
did not show this strategy, and increased their relative excretion of uric
acid instead of ammonia. It is possible that such costly nitrogen waste
disposal is only found in species that are not adapted for long-term fasting.
As observed previously by others (e.g. see
Hannaford et al., 1982),
rabbits showed a particularly high rate of nitrogen excretion and this may
also be related to the very high extraction of dietary protein afforded by
coprophagy (Thacker and Brandt,
1955
).
Conclusions
This study shows that, apart from their notorious capacity for hibernation,
woodchucks are particularly well adapted for normothermic fasting. Their
unusual ability to cope with prolonged food deprivation is based on a series
of integrated mechanisms eliciting deep metabolic depression and a rapid
change in fuel selection to spare limited protein reserves. The few studies
available on prolonged fasting suggest that such an ability for depressing
metabolism - to what could be minimal levels still compatible with
normothermic life - may be common among mammals. In contrast, extreme protein
sparing as demonstrated here in woodchucks, appears to be a unique metabolic
feature of the fasting champions.
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Acknowledgments |
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Footnotes |
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