Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil 05508-900
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ABSTRACT |
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To study the thermal response of
interscapular brown fat (IBF) to norepinephrine (NE),
urethan-anesthetized rats (1.2 g/kg ip) maintained at 28-30°C
received a constant venous infusion of NE (0-2 × 104 pmol/min) over a period of 60 min. IBF temperatures
(TIBF) were recorded with a small thermistor fixed under
the IBF pad. Data were plotted against time and expressed as maximal
variation (t°C). Saline-injected rats showed a decrease
in TIBF of ~0.6°C. NE infusion increased
TIBF by a maximum of ~3.0°C at a dose of
104 pmol · min
1 · 100 g body
wt
1. Surgically thyroidectomized (Tx) rats kept on 0.05%
methimazole showed a flat response to NE. Treatment with thyroxine
(T4, 0.8 µg · 100 g
1 · day
1) for 2-15 days normalized mitochondrial UCP1
(Western blotting) and IBF thermal response to NE, whereas iopanoic
acid (5 mg · 100 g body wt
1 · day
1) blocked the effects of T4. Treatment
with 3,5,3'-triiodothyronine (T3, 0.6 µg · 100 g
body wt
1 · day
1) for up to 15 days
did not normalize UCP1 levels. However, these animals showed a normal
IBF thermal response to NE. Cold exposure for 5 days or feeding a
cafeteria diet for 20 days increased UCP1 levels by ~3.5-fold.
Nevertheless, the IBF thermal response was only greater than that of
controls when maximal doses of NE (2 × 104 pmol/min
and higher) were used. Conclusions: 1) hypothyroidism is
associated with a blunted IBF thermal response to NE; 2)
two- to fourfold changes in mitochondrial UCP1 concentration are not necessarily translated into heat production during NE infusion.
brown adipose tissue; thermal response; thyroid hormones; uncoupling protein; cold exposure; cafeteria diet
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INTRODUCTION |
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BROWN FAT IS AN IMPORTANT SITE of nonshivering thermogenesis that is activated to supplement shivering and rapidly warms the body through arousal of hibernating or torpid mammals, or during cold exposure (9, 17). Its thermogenic capacity is due to a mitochondrial uncoupling protein (UCP1) that short-circuits the proton gradient across the inner mitochondrial membrane, bypassing the less abundant ATP synthase and thereby uncoupling fuel oxidation from the phosphorylation of ADP. The other members of the UCP group, namely UCP2 and UCP3, which are also capable of mitochondrial uncoupling, are present in brown fat as well as other tissues, but their physiological role is still controversial (5, 18, 32). Brown fat thermogenesis is triggered by norepinephrine (NE), which leads to a powerful stimulation of local lipolysis. Increased cytosolic fatty acids ultimately start the uncoupling process (21).
Facultative thermogenesis is positively influenced by thyroid hormones. Accordingly, it is well known that hypothyroid rats have decreased cold resistance and die within hours of being placed at 4°C. Even if injected with high doses of NE, they fail to increase oxygen consumption (38). Previous studies (24, 35), however, attributed only a permissive role to thyroxine (T4) in the NE-induced brown fat thermogenesis. The finding of type 2 deiodinase (D2) in brown fat (23) and the fact that it is stimulated severalfold by NE (33) have led to a better understanding of the active role of thyroid hormones in brown fat thermogenesis. Shortly after cold exposure is initiated, brown fat 3,5,3'-triiodothyronine (T3) concentration increases by about threefold (34), and nuclear T3 receptor occupancy reaches virtual saturation (3). Consequently, processes in brown fat that are primarily dependent on thyroid hormone are also activated during sympathetic stimulation of the tissue, and physiological changes that take place during cold and/or NE stimulation of the brown fat reflect a composite interaction between NE- and thyroid hormone-generated signals that eventually leads to sustained heat liberation. The major thyroid hormone-dependent pathways that have been characterized in brown fat so far are 1) adrenergic responsiveness, 2) UCP1 expression, and 3) lipogenesis (31).
The brown fat of thyroidectomized (Tx) rats is thermogenically inactive. cAMP generation in response to NE, mitochondrial content, and UCP1 expression are all greatly decreased. As a result, its metabolic response is greatly reduced (31). Because local D2 is increased severalfold during hypothyroidism, a single subphysiological dose of T4 is sufficient to rapidly normalize UCP1 mRNA levels. Indeed, the quick normalization of body temperature after a few hours of T4 administration was attributed to the restoration of UCP1 content in brown fat. However, we have recently found that the thermal response of interscapular brown fat (IBF) to NE infusion was normalized in T3-treated Tx rats even when its UCP1 content was only one-half of that found in intact euthyroid rats (7). More remarkably, when UCP1 was normalized in these T3-treated Tx rats, the thermal response of IBF was twice as high as that found in intact rats. These findings prompted us to expand our investigation concerning the relationship between brown fat mitochondrial UCP1 content and thermal response to NE infusion in various thyroid states and conditions known to affect UCP1 content, namely cold exposure and ingestion of a cafeteria diet.
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MATERIALS AND METHODS |
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Animals and diets.
Unless otherwise specified, all drugs and reagents were purchased from
Sigma Chemical (St. Louis, MO). Experiments were performed on male
Wistar rats weighing 150-200 g that were obtained from our
breeding colony. Studies were conducted in accordance with the highest
standards of humane animal care. Animals were maintained on a 12:12-h
dark-light cycle at 28-30°C and had free access to standard
animal chow and water. When exposed to cold (4°C for 5 days), the
animals were kept in individual cages with bedding. Surgical
thyroidectomy (Tx) was carried out under light ether anesthesia;
immediately after surgery, the animals were placed on 0.05%
methimazole in the drinking water and then were used 4 wk later. Body
weight was monitored at all times to check the arrest of growth in
hypothyroid animals. Some rats were implanted subcutaneously with a
continuous-release pellet (Innovative Research of America, Sarasota,
FL) of T4 (0.8 µg · 100 g body
wt1 · day
1) or T3
(0.15-1.0 µg · 100 g body wt
1 · day
1), as indicated in the text. Iopanoic acid
(IOP) was used at 5 mg · 100 g body wt
1 · day
1 when indicated.
IBF thermal response to NE infusion.
The response was determined as previously described in detail
(7). Briefly, all animals were anesthetized with urethan (1.2 g/kg ip) on the morning (9-10 h) of the experiment. A
polyethylene (P-50) cannula was inserted into the left jugular vein and
later used for NE infusion. IBF temperatures (TIBF) were
measured using a precalibrated thermistor probe secured under the brown
fat pad. Core temperature (TC) was measured with a colonic
probe. TIBF was measured during a period of ~15 min to
obtain a stable baseline, and then NE infusion was started. NE infusion
(0-2 × 104 pmol/min) was performed with an
infusion pump (Harvard model 2274) at a rate of 0.643 µl/min for
20-90 min. NE doses are expressed per 100 g body wt
throughout the experiments. Raw data were plotted over time and
expressed in terms of maximal changes in temperature over time:
TIBF (°C) vs. time (min).
Analytical procedures. At the end of the experimental period, rats were killed by decapitation, and the IBF was rapidly removed and processed for mitochondrial isolation (7). Procedures were performed at 4°C or in an ice-cold water bath as needed. Protein measurement was by the Bradford method (6). UCP1 was quantified after mitochondrial proteins were size-fractionated by 12% SDS-PAGE and identified by Western blotting, as previously described (2, 7). Serum concentrations of T4 and T3 were measured by RIA as described previously (7). For determination of plasma NE, venous blood samples were collected while the rats were still alive ~5 min before NE infusion was stopped. NE was measured by HPLC as previously described (8).
Statistical analysis. Results are expressed as means ± SD throughout the text and in Tables 1 and 2 and Figs. 1-5. Multiple comparisons were performed by one-way ANOVA followed by the Student-Newman-Keuls test.
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RESULTS |
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IBF thermal profile during NE infusion in intact rats.
After stabilization, TC and TIBF were 36.4 ± 0.2°C and 35.4 ± 0.3°C, respectively. The difference was
probably due to a more superficial localization of IBF. Figure
1A displays the profile of a
typical IBF thermal response to a 20-min infusion of three different NE
doses. TC is also shown as a reference. At the lowest NE
infusion rate (1 × 103 pmol/min), TIBF
increased rapidly, up to 0.5°C, and TC increased less,
only to 0.1°C. In the next set of animals, NE was infused at a higher
rate (2 × 103 pmol/min), and the rise in
TIBF and TC was steeper and reached higher
maximal values, ~0.9 and 0.3°C, respectively. The highest NE
infusion rate (5 × 103 pmol/min) triggered the
maximum temperature variation of ~1.2°C in IBF and of 0.40°C for
TC. Regardless of the NE dose used, once infusion ended,
IBF temperatures decreased rapidly during the next 20 min, whereas
TC normalization was much slower. Next we performed a
time-response curve using the NE dose of 5 × 103
pmol/min. The results are shown in Fig. 1B. There was a
progressively higher IBF thermal response to NE with time, up to 90 min, when a plateau was reached at ~2.2°C. Similar results were
observed with TC except that the plateau was ~0.7°C.
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Effects of thyroid status on IBF responsiveness to NE.
On the basis of conditions discussed above, we used intact rats to
perform a dose-response curve to NE by plotting the maximal change in
TIBF (TIBF) vs. the NE infusion rate, which
varied from 0 (saline) to 104 pmol/min and lasted 60 min.
As shown in Fig. 2A, plasma NE
concentration increased progressively at every increase in NE infusion
rate regardless of the thyroid status of the animals. The corresponding IBF thermal responses are presented in Fig. 2B. Infusion of
saline into anesthetized rats resulted in a progressively lower
TIBF that reached
0.6 ± 0.2°C at the end of the
infusion period. A positive IBF thermal response was only detected in
rats infused with 5 × 102 pmol/min NE. From that dose
on, the IBF thermal response was progressively greater with the
increase in NE infusion rate, and the curve obtained had a typical
sigmoid shape (Fig. 2B). The maximum
TIBF
obtained was ~3°C at an NE infusion rate of ~104
pmol/min. A plateau could not be reached, because higher NE infusion rates caused the rats to have difficulty in breathing and to experience sudden death. Infusion of selective adrenergic agonists, i.e., isoproterenol and phenylephrine, over an equivalent dose range, gave
similar results to the NE infusion, and all thermal responses were
blocked by propranolol (50 mg/kg) given 30 min before the experiment
(data not shown).
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Time frame of the T4 effects in Tx rats. Correlation
with UCP1 concentration.
On the basis of these results, we decided to investigate further the
time frame involved in the normalization of the IBF thermal response to
NE in Tx rats when T4 is used and to correlate the results
with UCP1 concentration. We did the same thing with T3, and
the results are shown in the next section. Therefore, Tx rats were
treated with a physiological replacement dose of T4
(0.8 µg · 100 g
body wt1 · day
1) for up to 15 days. The results are shown in Table 2
and Fig. 3A.
Serum concentrations of both iodothyronines increased progressively with time and were normalized by 5 days (Table 2). As above, the
administration of T4 was rapidly associated with a
restoration of the IBF thermal response. Basically by 1 day the IBF
response was half-maximum, and by 2 days it was normal. Longer periods on T4 did not result in greater IBF thermal response.
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Time frame of the T3 effects in Tx rats. Correlation
with UCP1 concentration.
A similar strategy was used with T3 administration. In this
case, however, we used twice the physiological replacement dose. Therefore, Tx rats were treated with T3 (0.6 µg · 100 g body
wt1 · day
1) for 1-15 days. At
the end of each period, we measured the IBF thermal response to NE
infusion at various rates. The results are shown in Fig.
4A. As
before, Tx rats showed a flat response to NE infusion regardless of the
dose administered. On the other hand, 1 day of treatment with
T3 caused a significant thermal response that increased
with the duration of treatment. By 15 days of T3
administration, the IBF thermal response was not significantly different from that of intact rats. It is interesting to note that the
highest effects of T3 treatment were detected in the animals infused with the highest dose of NE (Fig. 4A). Next,
the IBF thermal responses were plotted against UCP1 concentration (ng/µg; Fig. 4B) and IBF UCP1 content (mg/pad). First, it
is notable that, regardless of the duration of the T3
treatment, the mitochondrial UCP1 concentration or the IBF UCP1 content
was never normalized, staying always ~40% below the value seen in
intact rats. Regardless of the NE dose used, there was a positive
correlation between UCP1 concentration and IBF UCP1 content vs. IBF
thermal response. It is interesting, however, that with the lower
(102 pmol/min) and the intermediate (103
pmol/min) NE doses, the maximum IBF thermal response did not reach the
levels seen in intact rats. It was only with the highest NE dose
(104 pmol/min) that the IBF response was normalized, even
though the mitochondrial UCP1 concentration and UCP1 IBF content were
equivalent in all three groups of rats. What is remarkable is that a
normal IBF thermal response was obtained in rats that had only ~60%
of the UCP1 found in intact rats.
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Effects of cold exposure or feeding a cafeteria diet on the IBF
thermal profile during NE infusion in intact rats.
The next set of experiments was designed to investigate further the
correlation between IBF UCP1 concentration and its thermal response to
NE infusion. Therefore, we studied the IBF thermal response of
cold-exposed rats (5 days) or rats fed a cafeteria diet (20 days), two
conditions known to increase UCP1 concentration. In fact, UCP1
concentration was found to be 154 ± 23 ng/µg protein in the
cold-exposed rats and 165 ± 25 ng/µg protein in the rats fed a
cafeteria diet, respectively 3.4- and 3.6-fold higher than in intact
rats. Figure 5A shows that the
IBF NE-stimulated thermal profile of cold-exposed rats was very similar
to that of intact rats, except that with the higher NE doses the
maximal TIBF was >6°C higher than that in the rats
infused with saline, exceeding by ~3°C the response observed in
intact rats. A similar finding was detected in the rats fed a cafeteria
diet, which is shown in Fig. 5B, except that in this case a
small difference between the two curves was observed with the lower
doses of NE as well.
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DISCUSSION |
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Brown fat has an enormous capacity to generate heat, which is illustrated here by the ~3°C rise in TIBF of intact rats during maximal NE infusion and by similar reports in the literature (8, 16, 20). The brown fat of Tx rats, however, is known to present biochemical characteristics of impaired thermogenesis (2, 4). Accordingly, in the present study we found that the TIBF response to NE in Tx rats was remarkably flat. Indeed, the IBF thermal response was not only decreased, as other important markers of brown fat thermogenesis, but was abolished. As an example, even though the brown fat mitochondrial UCP1 content of Tx rats was reduced compared with intact rats, it was clearly detectable and alone could not explain the flat thermal response. It is likely, therefore, that rather than an isolated UCP1 insufficiency, the lack of thermal responsiveness to NE in Tx rats is a combination of multiple deficiencies, including decreased adrenergic responsiveness (10, 27-30).
In the present study, we showed that the lack of IBF thermal response to NE in Tx rats was improved after 24 h and completely restored after 48 h of physiological replacement with T4. So whatever shortcomings had developed during hypothyroidism were rapidly reversed by T4 administration. In previous studies, we found that within 24-48 h of physiological replacement with T4, UCP1 gene transcription (1, 26) mRNA levels (2) and mitochondrial concentration (2, 4) were restored in Tx rats. However, the physiological significance of those changes in terms of capacity of heat production has not been ascertained. Nevertheless, it is not clear how much of the brown fat thermal responsiveness to NE in intact or T4-treated Tx rats is determined or limited by UCP1 content.
To address this issue, we set out to study mitochondrial UCP1 and NE-induced IBF thermogenesis during treatment with thyroid hormones. Replacement with T4, at a dose equal to the daily production rate, rapidly normalized both UCP1 and thermal responsiveness to NE. Treatment with IOP, a D2 inhibitor, blocked the effect of T4, confirming our findings that T3 concentration in brown fat is strongly influenced by the local T4-to-T3 conversion (3, 11). By virtue of being severalfold stimulated in Tx rats, the brown fat D2 minimizes the effects of hypothyroidism and restores brown fat euthyroidism earlier than in most tissues (4).
To study the effects of T3, we purposely chose a dose (~2
times its daily production rate; 0.6 µg · 100 g body
wt1 · day
1) that would cause
systemic hyperthyroidism but not be high enough to restore euthyroidism
to the brown fat. This dose of T3 results in a nuclear
T3 receptor occupancy of ~50% in brown fat, which is
similar to that of most tissues but low for brown fat (4). This is because in intact rats, the brown fat D2 sustains a higher degree of nuclear T3 receptor occupancy [~70%;
(3)], a situation that can only be reproduced in Tx rats
if they receive replacement treatment with T4, or if
T3 is given at a dose of 1.2 µg · 100 g body
wt
1 · day
1, ~4 times the
daily production rate (4). The strategy led us to picture
a unique condition in which the thermogenic potential of UCP1 is
clearly amplified by other factor(s). These T3-treated Tx
animals presented a time-dependent increase in UCP1 levels that reached
only 25-30 ng/µg protein after 15 days, still ~40% lower than
intact rats. Nevertheless, there was a detectable increase in the brown
fat thermal response at every change in UCP1 level, even when these
increments in UCP1 were only minimal and barely significant. In
addition, despite having much lower mitochondrial UCP1 levels, these
T3-treated Tx rats reached an IBF thermal response to NE
equivalent to the intact or T4-treated Tx rats. It is
remarkable that IBF pads containing nearly a twofold difference in
their UCP1 pools (T4-treated vs. T3-treated Tx
rats) could have equivalent thermal responses to NE infusion.
A closer look at our findings, however, reveals that with lower doses
of NE (103 or 102 pmol/min), the IBF thermal
response of T3-treated Tx rats was not normalized,
remaining significantly below that observed in intact or
T4-treated rats. Only during maximal NE stimulation (104 pmol/min) was the IBF thermogenesis normalized,
raising the logical suspicion that brown fat adrenergic responsiveness
plays a regulatory role under these conditions. Although there are
coexisting 1-,
2-, and
3-adrenergic receptor subtypes in brown fat, activation of the
3-subtype is predominantly responsible for the
thermogenic responses (15, 41). These
receptors have a lower affinity for NE and, unlike
1 and
2, are not sensitive to homologous-mediated desensitization.
Brown fat adrenergic responsiveness is known to be negatively
correlated with local sympathetic activity (31). Cold
exposure, for example, decreases the adrenergic responsiveness of brown fat, an effect that has been ascribed to downregulation of
3-receptors and to diminished Gs protein
(14, 37). Thyroid status is also known to
regulate brown fat sympathetic activity and, hence, its adrenergic
responsiveness. Prolonged hypothyroidism is accompanied by increased
brown fat sympathetic tone (39, 40) and
decreased adrenergic responsiveness (27, 30),
whereas the opposite is observed during hyperthyroidism
(36). Work from Silva's laboratory (10,
28, 29) and others (25) has
indicated the existence of a postreceptor defect that leads to a
drastic reduction of cAMP generation in brown fat of hypothyroid rats
in response to NE. Combined with the low UCP1, this defect helps to
explain our first finding, i.e., the flat IBF thermogenic response to NE.
To understand the differences of IBF thermal responsiveness between T4- and T3-treated rats, it is important to keep in mind that the sympathetic activity and adrenergic responsiveness in the brown fat of these animals were different. T4-replaced Tx animals eventually restored their euthyroid status (systemically and at the brown fat level) so that UCP1 increase was followed by a decrease in brown fat sympathetic activity and normalization of its adrenergic responsiveness. On the other hand, the T3-treated Tx rats had, in fact, systemic hyperthyroidism (the T3 dose was twice the physiological replacement), which decreases brown fat sympathetic activity. It is therefore likely that the resulting increased adrenergic responsiveness allowed a normal thermogenic response to NE, even though the UCP1 levels were 50% lower.
To identify other conditions in which the IBF thermal response could be modulated at a pre-UCP1 level, we set out to evaluate NE-induced brown fat thermogenesis in rats exposed to cold or fed a cafeteria diet, both conditions in which the UCP1 and the sympathetic tone of brown fat are increased. As expected, both experimental groups had a ~3.5-fold increase in brown fat UCP1. However, particularly in the cold-exposed rats, the IBF thermal profile in response to NE infusion was very similar to that in warm-acclimated rats, except when high doses of NE were used. It is therefore clear that, within most of the NE dose range used, the thermal responsiveness of the IBF was limited to the values found in the warm-acclimated rats. It is notable that this happened in brown fat that had ~3.5 times more UCP1. Then, as if an escape had occurred, the TIBF increased ~3°C above what was observed in the warm-acclimated animals. A similar phenomenon was observed in the cafeteria-fed rats, except that TIBF was slightly above control values throughout the thermal profile. Nevertheless, the major difference in thermal response was only seen when high doses of NE were used.
Given the fact that thermal responsiveness of brown fat to NE infusion was measured during a relatively short period of time (60 min), it is possible to speculate about the involvement of the masking/unmasking mechanism of UCP1 nucleotide binding sites (13, 19). Unmasking is triggered by fatty acids that interact with UCP1 so as to increase the conductance of protons. The concentration of fatty acids is regulated by the activity of hormone-sensitive lipase (HSL), itself activated by NE. It is possible that, under our experimental conditions, changes in brown fat adrenergic responsiveness influenced NE-induced HSL activity, modifying the UCP1 unmasking phenomenon and therefore contributing to the poor correlation between UCP1 levels and brown fat thermal responsiveness.
In conclusion, the present study exposed, for the first time, physiological situations in which there is a lack of correlation between UCP1 content and thermal responsiveness of brown fat to NE. Under conditions in which the thyroid status was modified or the brown fat was stimulated by cold exposure or feeding a cafeteria diet, there were substantial changes in UCP1 mitochondrial concentration that did not necessarily translate into heat production during NE infusion. Our data support the concept that brown fat adrenergic responsiveness is an important pre-UCP1 modulating step that can strongly up- or downregulate brown fat thermogenesis and help the achievement of thermal homeostasis.
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ACKNOWLEDGEMENTS |
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We are grateful to José Luiz dos Santos and Ademar Pettri Filho for technical support.
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FOOTNOTES |
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This work was partially supported by a grant from Fundacão de Amparo a Pesquisa do Estado de São Paulo.
Address for reprint requests and other correspondence: A. C. Bianco, Brigham and Women's Hospital, HIM Bldg., Rm. 550, 77 Ave. Louis Pasteur, Boston MA 02115 (E-mail: acbianco{at}bics.bwh.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 22 December 1999; accepted in final form 8 March 2000.
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