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Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Oxygen
consumption (
O2)
was measured in normoxia as ambient temperature
(Ta) was lowered from 40 to
15°C, at the rate of 0.5°C/min (thermoneutrality ~33°C).
In 2-day-old rats born in hypoxia after hypoxic gestation, the
Ta-O2
relationship was as in controls; their interscapular brown adipose
tissue (IBAT) was hypoplastic (less proteins and DNA), with lower
concentration of the mitochondrial uncoupling protein
thermogenin. In 8-day-old rats exposed to hypoxia
postnatally (day 2 to
day 8), at any
Ta below thermoneutrality
O2 was higher than in
controls; also, in this group IBAT was hypoplastic with decreased
thermogenin. Additional measurements under various
experimental conditions indicated that the increased thermogenic
capacity was not explained by the smaller body mass and increased blood
oxygen content or by the eventuality of intermittent cold stimuli
during the chronic hypoxia. On the other hand, chronic hypercapnia (3%
CO2 in normoxia, from
day 2 to day
8) also resulted in increased normoxic thermogenesis. We conclude that chronic hypoxia in the perinatal period
1) reduces IBAT mass and
thermogenin concentration and
2) can increase the newborn's thermogenic capacity because of stress-related mechanisms not specific to hypoxia.
brown adipose tissue; hypercapnia; perinatal hypoxia; uncoupling protein thermogenin; undernourishment
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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ACUTE HYPOXIA is known to interfere with thermoregulatory mechanisms in both newborn and adult mammals (17). In newborn rats, thermogenesis, which is largely contributed by the calorigenic properties of the brown adipose tissue (BAT), can be suppressed even by moderate hypoxia (15, 24, 33).
Whether the effects of neonatal hypoxia on thermogenesis can persist on return to normoxia is a question of both biological and clinical interest. The results, however, are difficult to anticipate in view of the complex interplay of numerous factors. Thermogenesis could be compromised because the inhibitory effects of hypoxia on growth and tissue development are likely to include the BAT, hindering thermogenesis, which normally undergoes a rapid postnatal development (5, 15). In addition, because of the growth retardation, the underdeveloped newborn has higher body surface-to-mass ratio, which, in the cold, favors heat dissipation and a drop in body temperature.
On the other hand, the larger O2-carrying capacity induced by chronic hypoxia may increase the newborn's thermogenic response to cold. In fact, there are data suggesting that in newborns the peak, or "summit," metabolic response to cold may be limited by the availability of O2 (10, 16, 21). In addition, the decrease in body temperature during hypoxia can provide a stimulus to BAT growth and its uncoupling protein (UCP) thermogenin, as in animals acclimatized to cold (6-8, 14); this may eventually favor a calorigenic response to cold greater than in newborns never exposed to hypoxia.
Hence, after chronic hypoxia, on return to normoxia the newborn's thermogenic capacity should reflect the interplay of various processes, among which of paramount importance would seem to be the changes in BAT tissue itself, the increased blood O2 capacity, and body growth retardation.
The present experiments were conducted on normoxic 2-day-old rat pups
born from dams exposed to hypoxia through gestation and on normoxic
8-day-old rat pups exposed to hypoxia postnatally. O2 consumption
(O2) was measured in normoxia
at different ambient temperature
(Ta) values. The results
indicated that the thermogenic response was minimally altered by
prenatal hypoxia, whereas it was greater than control in the 8-day-old
pups postnatally exposed to hypoxia. In either case, BAT mass and the
UCP thermogenin were decreased. In an attempt to understand the role of
various factors possibly contributing to the greater thermogenic
response at day 8, additional
measurements were conducted on separate groups of same-age pups with a
postnatal history of intermittent separation from the mother,
undernourishment, chronic hypoxia with artificial reduction in blood
mass and hematocrit, or sustained hypercapnia.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experiments were conducted on Sprague-Dawley rats, after approval from the Animal Ethics Committee of this Institution.
Experimental groups.
All litters were born in the laboratory; on day
2, they were culled to 10 pups/litter, with only the
exception of the oversize litters for the undernourished group, which
had 20 pups/litter. The general protocol consisted of
measurements of O2 at
different Ta in experimentally
treated 2-day-old pups and 8-day-old pups and in the corresponding
same-age controls.
Treatments. Chronic hypoxia was obtained by placing the pregnant rat (in the case of prenatal hypoxia) or the litter with the dam (in the case of postnatal hypoxia) in a hypobaric chamber (12) at a barometric pressure of 440 mmHg (inspired PO2 ~92 Torr, Ta 24°C), which would correspond to an inspired fractional O2 concentration of ~12% in normobaric conditions. The chamber was opened for ~20 min every 2-3 days for cleaning and replenishing food and water.
Reduction in blood mass was performed in some pups of the hypoxic litters. To this end, in the early morning of day 8, the pup was anesthetized with halothane, and a small incision was made on the ventral side at the base of the tail. The tail artery was cut, and blood was collected in microtubes. The wound was then sealed with surgical glue, and the pup was returned to the dam. The whole procedure lasted ~5 min. About one-half of each litter was treated similarly, but the tail artery was not cut and blood mass was not reduced (sham operated). To test the effect of reduced body growth, some litters were maintained in normoxia but doubled in size (20 pups instead of the usual 10). In other normoxic litters we wanted to test the effects of periodic separation from the mother. For this purpose the whole litter was separated from the dam three times a day, for the duration of 1 h each, and during this time they were maintained at Ta of 23-24°C. Chronic hypercapnia was obtained by placing the litter with the dam from postnatal day 2 to day 8 in a 41-liter Plexiglas chamber in which a gas mixture of 3% CO2 in air was delivered at the rate of 1,250 ml/min, controlled by a precision flowmeter. Temperature and humidity of the chamber were as for controls and the other experimental conditions. CO2 concentration in the chamber was continuously monitored by a CO2 analyzer (model LB-2, Beckman, Anaheim, CA), and the output was recorded on paper.Measurements.
O2 (ml
STPD/min) was measured by an open-flow
system (11). The pups, in sets of two, were placed in a respirometer,
which consisted of a plastic transparent 75-ml container of cylindrical shape (15). The flow of air through the respirometer was controlled by
a precision flowmeter; inflowing and outflowing gases were sampled,
passed through a drying column (Drierite), and monitored by a
calibrated infrared CO2 analyzer
(model LB-2, Beckman) and a polarographic
O2 analyzer (model OM-11,
Beckman). Gas concentrations were displayed on a computer monitor
during on-line acquisition, and
O2 was calculated from the
flow rate and the inflow-outflow O2 concentration difference,
averaged over several minutes. Ta was monitored by two tungsten-constantan thermocouples (model DP30,
Omega, Stamford, CT) placed at the opposite ends of the respirometer.
To construct the
Ta-O2
relationship, we followed the same protocol previously adopted (15,
26). The rats were placed in the respirometer previously set at
Ta of 35°C, by adjusting a
heating lamp 13 cm in diameter. Because the heating source was large
compared with the size of the respirometer, regional
Ta differences were minimal.
During the following 10 min, Ta
was gradually increased to 40°C, and at this
Ta measurements were begun.
Ta was gradually decreased by
adjusting the distance of the heating lamp and placing cold pads on the
outer surface of the respirometer. The rate of
Ta change was 0.5°C/min (Fig.
1) and identical for all protocols. In the
8-day-old rats, colonic temperature was measured by fine
tungsten-constantan thermocouples (model DP30, Omega), immediately
before and after the O2
measurements, and was taken as representative of body temperature
(Tb).
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4 g, immediately frozen
in liquid nitrogen, and stored at 
80°C for later biochemical
analysis.
About 60-100 mg of IBAT were used for determination of the total
protein concentration. In the 2-day-old groups, two to four samples
from different animals were pooled together to reach the critical mass
necessary for the biochemical tests. For statistical analysis, these
pooled samples were considered as one. Sample homogenization and
protein extraction were as previously described (19, 20). Pellets were
resuspended in the extraction buffer, and the whole extraction was
repeated three or four times until the protein concentration of the
final resuspended pellet, assayed spectrophotometrically, was so low
compared with that of the supernatant (<1%) that all proteins were
considered extracted from the IBAT sample.
The electrophoretic separation of the proteins, for identification of
the mitochondrial UCP thermogenin and the cytoskeleton protein
actin, was done in the main groups of rats, i.e., the 2-day-old and
8-day-old hypoxic groups and corresponding controls. Protein separation was obtained by SDS-PAGE. Transfer to solid support
and immunoblotting (Western blot) were done according to standard
techniques, with a protocol identical to that previously adopted (19,
20). Individual samples were loaded in alternate order among groups.
Each sample was run at least three times, on different gels, with
constant volume loads of 3 to 7 µg of proteins, which were within the
linear portion of the optical density-load relationship. Two lanes per
gel were loaded with a protein sample prepared by combining subsamples
of all the rats of the control group; this was done to have a constant
reference sample on all membranes. Running conditions were 200 V
(constant voltage) for 1 h, in an ice-filled bucket. Transfer
conditions were 100 V for 60 min in the cold. After blocking, the
membrane was incubated with primary rabbit antibody from rat's brown
fat, anti-UCP (1:7,500, kindly donated by Dr. Teruo Kawada, of Kyoto University, Kyoto, Japan), and rabbit anti-actin (Sigma A-2668; 1:7,500). To visualize the primary antibody, we used the goat anti-rabbit immunoglobulin (secondary antibody, 1:5,000) conjugated to
alkaline phosphatase. The enzyme catalyzed a colorimetric reaction when
the appropriate substrate was added (Promega protoblot II A System).
The band densities were quantified from the dried membranes by use of
the BioImage scanning system with Whole Band analysis software
(Millipore on a Sun-Unix workstation), by using a 12-step optical-density wedge for external calibration. Video
images of the membranes were digitized, and integrated optical
densities of the individual bands were computed after delineation of
the regions of interest with an interactive cursor control. Data were expressed as UCP/actin ratio, as well as in percent of the reference control sample; for each animal the results of the various loads were
averaged, and, from these averages, means were calculated for each
group. From a portion of the original IBAT sample, DNA concentration
was evaluated spectrophotometrically against commercially available
standards, with the use of the diphenylamine extraction method (27).
Statistical analysis.
The number (n) of animals or of
samples for any particular measurement is presented in the pertinent
sections of RESULTS, Tables 1 and 2,
and Figs. 1-5. In the case of the
Ta-O2
relationships, n refers to the number
of sets, each comprising two pups. Data are presented as group means ± SE. Graphic representation of the Ta-O2
relationships also includes the 95% confidence intervals. Direct
comparison between two sets of data was done by two-tailed t-test.
O2
functions, two approaches were adopted to assess significant
differences between experimental and control curves. The
first approach aimed to assess differences in the overall responses to
either cold or warm conditions; 33°C was chosen as the
Ta value separating cold and warm
because it represents the lower end of thermoneutrality in the newborn rat (15). For each experiment, the
Ta-O2
relationship was plotted by using a fixed scale of coordinates; the
area under the curve, which represents the total
O2 used, was digitized, with a
graphics tablet connected to a minicomputer, over the
Ta ranges 15-33°C and
33-40°C. The variability among repeated analysis of the same
curve was <1%. A significant difference between the means of two
groups of rats was then tested by two-tailed
t-test.
The second analytic approach aimed to a more specific comparison of the
Ta-O2
curves (15). To assess whether two curves differed significantly from
one another (e.g, control vs. experimental, Fig.
2), y-axis
values were taken at the x-axis value
corresponding to the minimal difference between the two curves and were
tested for significant difference against the null hypothesis by
two-tailed t-test. A significant
difference at this x-axis value
indicated that the curve differed significantly at all
x-axis values. In the case of
nonsignificant difference, ANOVA was performed for the paired values at
Ta of 15, 20, 25, 30, 35, and
40°C, with post hoc contrasts with six Bonferroni's limitations.
Similarly, to test whether two functions did not differ from each
other, the y-axis values at the
largest difference between the two curves were analyzed for
statistically significant difference against the null hypothesis. If
the largest difference was found to be not significant, then the two
curves did not differ from each other at any
x-axis value. If the largest
difference was significant, ANOVA was performed for the paired values
at Ta of 15, 20, 25, 30, 35, and
40°C, followed by post hoc contrasts with six Bonferroni's limitations. In all cases, significant differences were defined at
P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Two-day-old pups, after hypoxic gestation.
At day 2, pups born from dams in
hypoxia for the whole gestation had lower body weight and higher
hematocrit and hemoglobin concentration than did controls (Table
1). The
Ta-O2
relationships did not differ significantly from controls (Fig.
2A), whether the areas under the
curve or levels of O2 at the
predetermined values of Ta
were statistically compared. The IBAT was hypoplastic, with
proportional reduction in DNA and protein content. The UCP thermogenin
was significantly reduced, by ~30%, whether examined as a percentage
of the whole protein content or relative to the concentration of the
cytoskeleton actin.
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Eight-day-old pups, after chronic hypoxia.
The
Ta-O2
relationship of the pups maintained in chronic hypoxia from
day 2 to day
8 was displaced above that of controls (Fig.
2B). The area underneath the
Ta-O2
curve was significantly increased both above and below 33°C; of the
six Ta values statistically tested, O2 was significantly
increased at 40, 30, 25, and 20°C.
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Undernourished rats.
These rats were raised in normoxia in large litters (20 pups/litter).
As the result, they grew less, and by day
8 their body weight averaged 11.1 ± 0.4 (SE) g
(n = 10), i.e., ~60% control, and
similar to the body weight of the chronic hypoxic group presented above. Their hematocrit was normal (36 ± 1%;
n = 16). The
Ta-O2 relationship was similar to controls above 33°C, whereas it was below controls over the range 33-15°C
(P < 0.05) (Fig.
3, undernourished); after ANOVA, post hoc
analysis indicated a significant difference from control at
Ta= 20°C
(P < 0.05) and 15°C
(P < 0.001).
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Rats with periodic maternal separation.
These rats were raised in normoxia and were separated from the dam for
1 h, three times a day, every day. At day
8 their body weight (19.2 ± 0.3 g;
n = 20) and hematocrit (35 ± 1;
n = 17) were as in controls. The area
of the
Ta-O2
curve (n = 5 sets), although it tended
to be displaced at the upper end of the controls' 95% confidence
intervals (Fig. 3, intermittent maternal separation), did not
statistically differ from control. After ANOVA, post hoc analysis of
the O2 levels at the six
selected Ta values indicated a
significant difference from control at 20°C
(P < 0.05).
Chronic hypoxia and reduced hematocrit.
Five sets of 8-day-old chronic hypoxic rats had a
reduction in blood mass and were compared with five sets of littermates that underwent a sham operation. Six-to-eight hours after the hemorrhage, hematocrit was significantly reduced (42 ± 1%,
compared with 48 ± 1% of the sham;
P < 0.0001). Body weight did not
differ significantly. The
Ta-O2
relationships of these two groups are presented in Fig.
4. No difference between the two curves was detected, irrespective of the type of statistical analysis.
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CO2 exposure.
Ten rat pups were maintained in 3%
CO2 after day
2. At day 8, body
weight (15.2 ± 1.0 g) was slightly less than in controls. Hematocrit (39 ± 1%) was also slightly increased and was similar to the value of the undernourished group. The area underneath the
Ta-O2
curve below 33°C was significantly greater
(P < 0.001) than in controls; post
hoc analysis revealed a statistically significant increase in
O2 above the control values
at 25, 20, and 15°C (Fig. 5).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In a previous study on the effects of hypoxia on BAT, we observed a reduction of the mitochondrial UCP thermogenin in 2- and 3.5-mo-old rats exposed to hypoxia for a few days or for many weeks, whereas no significant changes occurred in 25-day-old rats hypoxic for 4 days (20). In the present neonatal rats hypoxic for the whole gestation or for 6 days after birth, we have found BAT hypoplasia and a reduction in thermogenin. Hence, in combining these results, it would seem that hypoxia has an inhibitory effect on BAT as long as it is maintained for at least several days. The half-life of thermogenin is ~1 wk (9, 23); therefore, an effect on its tissue concentration with only a few days of exposure may be difficult to demonstrate, especially at weaning age, which in the rat corresponds to the time of maximal importance of BAT in thermogenesis (3). The newborn animal is often subjected to ambient cold stimuli, and in hypoxia its hypometabolic response results in a drop in Tb; in the fetus neither occurs, because the mother represents a constant heat supply, irrespective of the metabolic level of the fetus. Hence, the qualitatively similar effects on BAT between prenatal and postnatal hypoxia suggest that the hypoxic inhibition of thermogenin can occur even in the absence of Ta or Tb stimuli on nonshivering thermogenesis.
In newborns, compared with adults, shivering as a means of heat
production is an inefficient and rarely adopted mechanism (5), and in
the newborn rat it is probably absent. Huddling and
Ta selection are important
behavioral mechanisms against cold (1), which, by limiting the drop in
Tb, can enhance the thermogenic response (26). However, huddling cannot have been an important factor
in the present study, because the rats were studied in sets of only two
pups, and the uniformity of Ta in
the chamber excluded the possibility of behavioral choices. Hence, the
O2 responses of these newborn rats
to the lowering in Ta should
solely reflect their nonshivering (BAT) thermogenesis. The possibility that changes in the interscapular location of BAT did not represent changes in other BAT locations seems extremely improbable, in view of
the morphological, ultrastructural, and biochemical similarities of BAT
among different body locations (30, 31). It is therefore interesting
that the reduction in BAT mass and thermogenin was not accompanied by a
reduced thermogenic capacity, which, in fact, we found to be unaltered
in the prenatal-hypoxia group and increased in the postnatal-hypoxia
group. Previously, in mice chronically exposed to cold, it was noticed
that the characteristic increases in BAT mass and thermogenin were not
necessarily parallelled by an increase in the
O2 response to cold (32). A
mismatch between anatomic and biochemical changes of BAT and
whole-organism thermogenic capacity reflects the multifaceted action of
a prolonged stimulus. In the case of chronic hypoxia, in addition to
BAT thermogenesis, several parameters and functions are modified and
likely interfere with the thermogenic responses of the whole organisms.
Some possibilities we have experimentally addressed.
Chronic hypoxia decreases body growth; indeed the hypoxic rats had
lower body weight than did controls, as previously observed with either
prenatal or postnatal hypoxia (12, 18). Because smaller animals have
higher mass-normalized O2
than do larger animals, one possibility was that the increased
thermogenic capacity was the result of the lower body mass. The data
obtained in the normoxic pups raised in large litters (undernourished
group) would exclude this possibility. In fact, their body weight was
similar to that of the hypoxic pups, but their
O2 response to cold was less,
not more, than in controls. Underfeeding is known to decrease thermogenesis (13, 28), presumably because of the suppression of norepinephrine turnover rate in sympathetic innervated organs, including BAT (25).
Because not only the newborns but also the mothers were exposed to hypoxia, the possibility emerged that maternal behavior, including stress response and periodic neglect, affected the rearing of the pups. Previous observations of litters raised in 15 or 10% O2, with dams rotated daily to reduce the maternal exposure to hypoxia, indicated that maternal hypoxia had minimal impact on the growth of the pups (22). Nevertheless, we explored the eventuality of some effects on neonatal thermogenesis. Indeed, we found that periodic separation from the mother resulted in some increase in thermogenic capacity of the 8-day-old pups; however, this was also accompanied by BAT hyperplasia, opposite to what found with neonatal hypoxia. Intermittent maternal separation must have provided intermittent cold stimuli sufficient to stimulate BAT growth and the thermogenic capacity (8, 29). In conclusion, it would seem unlikely that the higher thermogenesis of the 8-day-old pups with a history of chronic hypoxia was contributed by maternal responses, because neither undernourishment nor intermittent maternal separation provided results compatible with what observed.
In newborns, including infants, hyperoxia raises
O2 (16, 21) and increases the
thermogenic response to cold (10), results that could be considered
consistent with the possibility of neonatal
O2 being limited by the
availability of O2. Hence, we
needed to consider the eventuality that the higher thermogenic capacity
of the 8-day-old pups exposed to hypoxia was due to their increased
blood O2-carrying capacity. The
experimental reduction in blood mass, which resulted also in a drop in
hematocrit, was inconsequential on the pups' thermogenic responses.
This result is not compatible with the idea of
O2 availability limiting neonatal O2; rather, it agrees with
the view that the neonatal metabolic level is set by regulatory
processes, a possibility that also emerged from an analysis of
O2-transport mechanisms during the hypometabolic response to acute hypoxia (24).
The 8-day-old pups exposed to hypercapnia had minimal, yet significant,
drops in body weight and increases in hematocrit, probably an
indication of some dehydration associated with the prolonged hyperpnea.
The important result was the major increase in thermogenic capacity,
similar to that of newborns exposed to chronic hypoxia; this was
accompanied by a small reduction in BAT mass. Hence, from the viewpoint
of the neonatal thermogenic capacity, a history of prolonged hypoxia or
hypercapnia had similar effects. Nonshivering (BAT) thermogenesis is a
hypothalamic-controlled function mediated by the sympathetic nervous
system, norepinephrine being the neurotransmitter acting on the
-adrenergic receptors of the adipocytes membrane.
Nonshivering thermogenesis is therefore one of the many functions
participating to the sympathetic alarm "fight or flight"
reaction. In fact, stress-induced hyperthermia has been demonstrated in
many species, including rats (37, also for references) and humans (4).
Although less studied than Tb, the
thermogenic processes also seem to be affected by stress (2, 34), which
is probably to be expected considering that stress activates the
preoptic thermoregulatory neurons (35) and increases sympathetic
activity (measured by norepinephrine turnover) to the BAT (36).
In conclusion, hypoxia, whether prenatal or postnatal, results in hypoplasia of BAT and in lower thermogenin concentration. Despite these effects on BAT, the thermogenic response to cold can be increased. This phenomenon, shared also by pups with a history of normoxic hypercapnia, most likely reflects the increased sensitivity of the sympathetic system to prolonged stress.
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ACKNOWLEDGEMENTS |
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This work was supported by funds from the Medical Research Council of Canada.
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FOOTNOTES |
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Address for reprint requests: J. P. Mortola, McGill Univ., Dept. of Physiology, Rm. 1121, 3655 Drummond St., Montreal, PQ, Canada H3G 1Y6 (E-mail jacopo{at}physio.mcgill.ca).
Received 13 November 1997; accepted in final form 18 February 1998.
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REFERENCES |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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;
n = 10 sets, 20 pups) were born from
dams exposed to hypoxia throughout gestation and were compared with
same-age controls (
; n = 10 sets,
20 pups). Experimental pups of day 8 (
; n = 5 sets of 2 pups each) and 8-day-old pups with repeated episodes of separation from
the mother during preceding 6 days (
; n = 5 sets of 2 pups each). Symbols are mean values; bars represent SE.
Dotted lines demarcate 95% confidence intervals of the control pups
from Fig. 
) and others with sham intervention (
).
Symbols are mean values of 7 sets of 2 pups each; bars represent SE.
Lines demarcate 95% confidence intervals. The 2 functions did not
differ significantly from one another.
