Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80–100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose-dependent fashion (log-linear regression P < 0.01, R2 = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 ± 24 min (means ± SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases.
- sympathetic nerve activity
- arousal and biological rhythm
the 12 hourly alternation between light and dark is so important in evolution and natural selection that circadian rhythmicity is manifest in probably all physiological variables. Ultradian rhythmicity (periodicity <24 h), also apparent in many physiological variables, may also be biologically important, since the amplitude of ultradian rhythms is usually of approximately the same magnitude as that of circadian rhythms (30, 49), and the amplitude of episodic ultradian increases becomes larger after lesions of suprachiasmatic nuclei that abolish circadian rhythms (1, 16).
Ultradian rhythmicity is apparent in brown adipose tissue (BAT) temperature in rats, with an interpeak interval of ∼80–100 min in the dark phase of circadian cycle (11, 40). The variation in BAT temperature is highly correlated with corresponding variations in body and brain temperature, and with phase-linked changes in arterial pressure, heart rate, and behavioral activity. All of these events are preceded by a sudden increase in the power of hippocampal theta rhythm, a marker for vigilance, arousal, and active engagement with the environment (3, 15, 54). The occurrence of phase-linked ultradian events has led us to hypothesize that they are dynamic physiological phenomena driven by the brain central command, integrated components of the active phase of the pattern that Kleitman (28) referred to as the basic rest activity cycle (BRAC).
BAT metabolism contributes substantially to variations in whole body temperature in rats (9). BAT thermogenesis is initiated when norepinephrine, released from sympathetic nerve terminals, acts at beta-3 adrenoceptors on BAT cells. In our recent report (40), the ultradian episodic increases in BAT temperature were larger than the corresponding increases in brain and body temperature, and there was a strong relationship between the amplitude of increases in BAT temperature and corresponding increases in body and brain temperature. Therefore, we hypothesized that BAT thermogenesis makes a substantial contribution to ultradian increases in brain and body temperature.
In the present study, we tested our hypothesis by determining whether inhibition of BAT thermogenesis with the beta-3 adrenergic receptor antagonist SR59230A decreases baseline BAT, brain, and body temperatures, and whether SR59230A interrupts the timing of ultradian episodic increases in BAT, brain, and body temperature in conscious rats. We also investigated the effect of SR59230A on tail skin blood flow and heart rate to assess the possibility that body and brain temperature changes reflect heat dissipation or changes in cardiac function (2, 21), and to control for the fact that SR59230A may interact with other subtypes of adrenoceptors (5, 7, 8, 23, 29). In additional experiments with anesthetized rats, we tested whether inhibition of BAT thermogenesis occurs without inhibition of BAT sympathetic nerve activity, the result to be expected if SR59230A acts directly on BAT.
MATERIALS AND METHODS
Experiments (male Sprague-Dawley rats, 302–485 g, n = 33) were conducted at Flinders University with the approval from the Animal Welfare Committee of Flinders University. All efforts were made to minimize the number of animals used and their suffering.
Surgical procedures for conscious rats study.
Animals were instrumented under general anesthesia (2% isoflurane in O2; Veterinary Companies of Australia, Marayong, NSW, Australia). After surgery, analgesia (5 mg/kg sc Rimadyl; Pfizer, West Ryde, Australia) and antibiotics (5 mg/kg sc Baytril; Bayer, Pymble, Ausralia) were administered, and animals returned to the animal house for at least 1 wk before experiments were carried out. Animals were maintained in quiet environments (a reverse 12:12-h light-dark cycle, lights on at 1900), and individually caged away from other rats with minimal human intrusions. Ambient temperature was maintained at a constant level, 24°C. Standard food and water were available ad libitum.
To measure iBAT, body, and brain temperatures, temperature probes were made from thermistors, as previously described (40). In each rat, the temperature probes were positioned in iBAT, in a dorsal extradural position near the confluence of the sagittal and transverse sinuses via craniotomy (for brain temperature), and in the peritoneal cavity (for body temperature). Wires from the temperature probes were attached to the head socket, and the signals were collected with a bridge amplifier (Biomedical Engineering, Flinders University, Adelaide, Australia). As previously described, the correct position of the iBAT probe for each rat used in the study was confirmed in a preliminary procedure in which animals placed for 30 min in a cold (5–10°C) environment showed an increase of at least 0.5°C in iBAT temperature (41).
In a different set of conscious rat experiments, rat tail artery blood flow was measured by a Doppler ultrasonic probe (Iowa Doppler Products, Iowa City, IA) chronically implanted around the base of the tail artery, with wires from the probe passing subcutaneously to the head socket, and with signal analysis (200 Hz sampling rate), as previously described (19, 43). In these rats, the ECG and body temperature were recorded via chronically implanted electrodes (TA11CTA-F40; Data Sciences International, Transoma Medical, St. Paul, MN).
Experimental design for study in conscious rats.
In triple temperature recordings of iBAT, brain, and body, all measurements were performed continuously over 48 h in a temperature-controlled cage under quiet environments (a 12:12-h light-dark cycle, lights on at 1900) and constant ambient temperature (24°C). The animal was transferred to this cage on the day of starting recording and left overnight. In the next day, SR59230A (1, 5, or 10 mg/kg ip) or water-vehicle (0.5 ml ip) was injected intraperitoneally during the dark phase, with each injection occurring in the 20-min time interval after a peak in iBAT temperature. Then, the animal was returned to the cage, and recording was ceased on the next day.
In heart rate, tail flow, and body temperature recordings, all measurements were performed continuously for at least 2 h before injection and left for at least 3.5 h. SR59230A (5 or 10 mg/kg) or water-vehicle (0.5 ml) was injected intraperitoneally.
Each animal was used in three or four experiments, with different doses of drugs. The animal was held manually during intraperitoneal injection of drugs. At least 3 days were allowed between experiments. To avoid serial effects, we used a rotational design. Standard food and water were available ad libitum during measurements.
40). The onset of each iBAT temperature increase was specified as the time of the first minimum value preceding the peak. Simultaneously recorded body and brain temperature (>0.2°C) were then searched for peaks occurring within ±20 min of a given iBAT temperature peak (40).
Surgical preparation for anesthetized rats study.
After a rat was anesthetized with isoflurane (2%; Veterinary Companies of Australia, Kings Park, NSW, Australia) via a nasal mask, its trunk and limbs were shaved, and an endotracheal tube was inserted via a tracheotomy. The right femoral artery and vein were cannulated for measurement of systemic arterial pressure and for intravenous drug administration, respectively. After the venous line was secured, isoflurane anesthesia was interrupted, and then a cocktail of urethane (400–800 mg/kg iv; Sigma-Aldrich, St. Louis, MO) and α-chloralose (40–80 mg/kg iv; Sigma-Aldrich) was injected (50 μl/min). Alpha-chloralose was dissolved in 10% 2-hydroxypropyl-β-cyclodextrin (Sigma-Aldrich). The level of anesthesia was maintained at a depth sufficient to abolish withdrawal reflexes. Supplementary doses of a cocktail of urethane (40 mg) and α-chloralose (4 mg) were given by a bolus injection when appropriate to ensure adequate anesthesia.
The rat was then mounted prone in a stereotaxic frame, and a hand-made water jacket was placed around the thorax and abdomen to maintain colonic temperature at 35–36°C and to alter the temperature of the trunk skin when needed. To record iBAT sympathetic nerve activity (SNA), the sympathetic nerves innervating iBAT were dissected, as described previously (42), and nerve signals were recorded with bipolar silver electrodes and a preamplifier (NL100; Digitimer, Welwyn Garden City, UK), amplified (gain 10,000; NL104 amplifier; Digitimer), and filtered (1–1,000 Hz; NL125 filter; Digitimer). The rat was paralyzed with d-tubocurarine [initially 0.3 mg iv (1–1.6 mg/kg), bolus; thereafter, 0.3 mg iv every 1–1.5 h; Sigma-Aldrich] and then ventilated artificially with 100% O2. The animal was allowed to recover from paralysis between doses, so that adequate anesthesia could be confirmed before paralysis was reestablished. End expiratory CO2 concentration (ExpCO2) was monitored continuously with CO2 analyzer (Normocap; Datex, Helsinki, Finland) and maintained between 3.5 and 4.5% (resting condition) by adjusting ventilation volume. The temperature of the contralateral iBAT, abdominal skin, and colon was measured with thermocouples (Type-T; Physitemp, Clifton, NJ) and an amplifier (TC-2000; Sable Systems, Las Vegas, NV).
2 signals were digitized at 1 Hz. The amplitude of iBAT SNA was expressed as total power spectral density between 0 and 20 Hz from the autospectra of sequential 5.12-s segments of iBAT SNA.
Experimental procedures for anesthetized rats study.
The truncal skin was cooled by perfusing cold (5–10°C) water through the jacket for a short (2–3 min) time period. The consequent increase in iBAT SNA was used to confirm that recording was from the nerves supplying iBAT (42); only animals displaying a reproducible iBAT SNA response to two consecutive skin-cooling episodes were used in further experiments. Warm (40–45°C) water was then reintroduced into the jacket to rewarm the truncal skin. The same cooling procedure was performed after SR59230A (5 mg/kg iv) or its vehicle was infused intravenously over 6 min. All parameters were monitored for at least 30 min. At the end of all experiments, the skin-cooling procedure was performed again. After the iBAT SNA increased, a ganglionic blockade with chlorisondamine chloride (10 mg/kg iv) was administered to confirm a loss of iBAT SNA, and thus to ensure that nerve recording was from postganglionic sympathetic axons.
SR59230A (Tocris Bioscience, Bristol, UK) was sonicated and dissolved in water, and warmed (35–37°C) before injection.
Data were analyzed with Igor Pro (WaveMetrics, Lake Oswego, OR), and with Statview (SAS Institute, Carey, NC). Group data were shown as means ± SE unless otherwise indicated. For example, data were shown as means ± SD for descriptive statistics. Student's t-test and factorial and repeated-measures ANOVA were used, with post hoc comparison with Fisher's protected t-test. The significance threshold was set at the 0.05 level. Linear regression was used to assess dose-response effects and relationships between different signals.
Ultradian variability in iBAT, brain, and body temperature.
Under undisturbed and quiet conditions in an experimental cage, iBAT temperature increased episodically, in association with increases in body and brain temperature (Fig. 1A). During a dark phase, before injection of SR59230A or vehicle, episodic iBAT thermogenesis occurred every 82 ± 36 min, amplitude 1.0 ± 0.4°C and time from onset to peak 27 ± 16 min (means ± SD, 259 episodes in 17 rats).
The increase in iBAT temperature was greater than the corresponding increase in brain and body temperature (1.0 ± 0.1°C, 0.6 ± 0.1°C, and 0.6 ± 0.1°C, respectively, P < 0.01, Fig. 1B), with significant linear regression between corresponding increases in iBAT and brain temperatures [log-linear regression, F(1,221) = 119.2, P < 0.0001, R2 = 0.35, Fig. 1C], and iBAT and body temperatures [log-linear regression, F(1,227) = 50.2, P < 0.0001, R2 = 0.18].
The maximum rate of iBAT temperature increases was significantly greater than the maximum rate in brain and body temperature increases (0.11 ± 0.01°C/min, 0.05 ± 0.01°C/min and 0.08 ± 0.01°C/min, respectively, P < 0.01, n = 40) (Fig. 1B).
Effects of SR59230A on basal temperatures and episodic ultradian temperature increases.
Injection of SR59230A (1, 5, or 10 mg/kg ip) dose-dependently decreased iBAT, brain, and body temperatures (log linear regression, P < 0.01, R2 = 0.3., 0.4, and 0.4, respectively, n = 10) (Fig. 2, A and B). In the highest dose of SR59230A (10 mg/kg), iBAT temperature decreased by 1.2 ± 0.2°C (from 38.1 ± 0.3°C to 37.0 ± 0.3°C, P < 0.01, n = 10) at 78 ± 12 min after the injection and returned to preinjection level within 160 min. There is a significant linear regression between corresponding fall in iBAT and brain temperatures (P < 0.05, Fig. 2C), and in iBAT and body temperatures (P < 0.05).
SR59230A interrupted episodic iBAT thermogenesis with similar effects on episodic brain and body temperature increases. SR59230A dose-dependently prolonged the intervals between the peak of the last episodic increase in iBAT temperature before injection and the peak of the first episode after the injection [log-linear regression, F(1,28) = 6.2, P < 0.02, R2 = 0.2] (Fig. 2D), and the intervals between the injection time and the peak of the first episode after the injection [log-linear regression, F(1,28) = 14.6, P < 0.001, R2 = 0.4].
Effects of SR59230A on iBAT sympathetic nerve discharges in anesthetized rats.
Under resting condition in anesthetized rats with a core temperature of 35.4 ± 0.7°C and a skin temperature of 36.1 ± 0.7°C (mean ± SD, n = 6), iBAT sympathetic nerve activity was absent or low. Perfusion of cold water (duration 2.5 ± 0.5 min, means ± SD, n = 6) through a water jacket around the animal's trunk decreased skin temperature by 6.0 ± 1.0°C (means ± SD, n = 6). The skin cooling caused a robust increase in iBAT sympathetic nerve activity (Fig. 3) and increased the contralateral iBAT temperature by 0.7 ± 0.2°C (from 33.9 ± 0.2°C to 34.5 ± 0.2°C, P < 0.05, n = 6). End-expiratory CO2 concentration was increased from 3.6 ± 0.2% to 3.9 ± 0.3% (P < 0.05, n = 6).
Vehicle (0.5 ml iv water) was administered after the first cooling episode, and then a second skin cooling was performed. The skin cooling caused an increase in iBAT sympathetic nerve activity (P < 0.01, n = 6) and increased the contralateral iBAT temperature by 0.8 ± 0.1°C (from 33.7 ± 0.2°C to 34.5 ± 0.2°C, P < 0.01, n = 6). End-expiratory CO2 concentration was increased from 3.6 ± 0.2% to 4.0 ± 0.2% (P < 0.01, n = 6).
SR59230A (5 mg/kg iv) was slowly administered for ∼5 min after the second cooling episode, and then the third skin cooling was performed after a 6-min observation time (Fig. 3A). The skin cooling caused a large increase in iBAT sympathetic nerve activity (P < 0.01, n = 6), without a significant change in end-expiratory CO2 concentration or in contralateral iBAT temperature (P > 0.05, n = 6). Adminstration of SR59230A did not significantly change basal iBAT sympathetic nerve activity (P > 0.05, n = 6). Interscapular BAT temperature did not change in a consistent manner during the 6-min observation time after the SR59230A (P > 0.05, n = 6). End-expiratory CO2 concentration did not change during administration of SR59230A, while it increased by 0.2 ± 0.1% (from 3.8 ± 0.2 to 4.0 ± 0.2%, P < 0.01, n = 6) during the 6-min observation time, remaining at the increased level, until after recovery from the skin-cooling response. Blood pressure decreased from 115 ± 4 mmHg to 57 ± 13 mmHg (P < 0.05, n = 6) during the administration of SR59230A and returned to preinjection level within 6 min after the end of the administration.
The skin-cooling response of iBAT temperature and expiratory CO2 started to recover at 72 ± 35 min (means ± SD, n = 6) after SR59230A (Fig. 3B). After this time, skin cooling again increased the iBAT temperature from 34.9 ± 0.2°C to 35.2 ± 0.2°C (P < 0.05, n = 6), and end expiratory CO2 concentration from 4.1 ± 0.3% to 4.5 ± 0.3%, (P < 0.01, n = 6).
Effects of SR59230A on basal heart rate and cutaneous blood flow in conscious rats.
Each rat was kept in an experimental cage for at least 120 min for habituation, and then SR59230A (5 or 10 mg/kg ip) or vehicle (0.5 ml ip water) was administered. SR59230A decreased body temperature dose-dependently (P < 0.05, Fig. 4). Body temperature reached the minimum value at 66 ± 5 min (for 5 mg/kg, n = 5) or at 88 ± 7 min (for 10 mg/kg, n = 7) after SR59230A. The low dose of SR59230A did not affect heart rate or tail artery blood flow. The high dose (10 mg/kg) caused a bradycardic response and a small fall in tail artery blood flow. Heart rate decreased from 347 ± 7 beats per minute (bpm) to 254 ± 20 bpm, (P < 0.01) at 23 ± 5 min (n = 7) after injection of SR59230A (10 mg/kg) and then returned to preinjection level within 60 min after the injection. Injection of vehicle did not affect baseline tail blood flow, heart rate, or body temperature during the 180-min observation period after the injection.
The episodic phase-linked ultradian increases in BAT, brain, and body temperature observed in the present study are similar to those reported in our recent study (40). We again documented that the amplitude of episodic increases in BAT temperature was substantially larger than corresponding brain and body temperature amplitudes, and again, there was a significant linear relationship between the amplitude of each BAT temperature increase and the amplitude of each corresponding body and brain temperature increase. In the present study, we also demonstrated that the maximum slope of the increases in BAT temperature during each ultradian episode was substantially greater than the corresponding maximum slope for body and brain. We also applied the same regression analysis to our previous data (40) and demonstrated the same result. A substantially greater rate of increase in BAT temperature compared with other regional temperatures is strong evidence that the BAT temperature increases are due to local BAT thermogenesis, not to passive heating from other bodily sources.
Direct continuous measurement of BAT temperature in the conscious animal under quiet, undisturbed conditions is a simple and robust method of assessing physiologically relevant BAT thermogenesis. Ours is the first report of the effect of the beta-3 adrenoceptor antagonist SR59230A on iBAT thermogenesis in such conditions. SR59230A decreased basal BAT temperature, accompanied by a decrease in body and brain temperature, and SR59230A interrupted the episodic ultradian increases in iBAT, body, and brain temperature. Thus, the present study further supports our previous notion that episodic ultradian BAT thermogenesis contributes substantially to the ultradian rhythmicity in whole body and brain temperature in rats (40).
It is well established that cold exposure increases BAT sympathetic discharge and triggers BAT thermogenesis, producing heat that contributes substantially to the maintenance of body temperature in rats (4, 9, 35). In our anesthetized animal preparation, cold exposure via skin cooling triggered increased iBAT sympathetic discharge, iBAT temperature, and the concentration of expired CO2 in the expected manner. Unexpectedly, in the anesthetized animal, the effect of SR59230A seemed to include an agonist component (see discussion below) so that baseline levels of BAT temperature and expired CO2 concentration were sometimes increased. Nevertheless, in agreement with our hypothesis, after administration of SR59230A, but not after vehicle, skin-cooling increased iBAT sympathetic activity without accompanying increases in iBAT temperature and expiratory CO2 concentration. After a recovery period of ∼60-min skin cooling once again caused increases in all three variables. Our work of simultaneous recording of iBAT temperature and iBAT SNA is actually the first in vivo documentation that SR59230A, by a direct action at the level of BAT itself, antagonizes physiologically induced (cold exposure) increases in BAT temperature.
Brown adipose tissue can increase its metabolic rate many times, so that increases in BAT thermogenesis substantially increase whole body metabolic rate and body temperature (9). Brown adipose tissue-ablated mice have body temperature 0.9°C less than wild-type mice (27). Since beta-3 adrenoceptors were reported as a novel beta-adrenoceptor subtype (17), their role on BAT thermogenesis has been documented in many studies (see reviews in Refs. 9, 12, and 32). Northern blot analysis indicates that beta-3 adrenoceptors are abundantly expressed only in brown and white adipose tissue (22, 36). Beta-3 adrenoceptors have been shown to be involved in uncoupling protein 1 (UCP1) upregulation and BAT thermogenesis in isolated brown adipocyte or cell culture preparations (10, 56, 57). Upregulation of UCP1 elicited by a beta-3 agonist (in vitro study) or by cold exposure (in vivo study) is inhibited by SR59230A (46, 52). In awake UCP-1-ablated mice, thermogenesis elicited by beta-3 agonists is blunted (18). SR59230A prevented BAT thermogenesis induced by selective beta-3 receptor agonists in anesthetized rats (33). Thus, both in conscious and anesthetized animal experiments, it is likely that SR59230A binds beta-3 receptors expressed on BAT, thereby, blocking sympathetically mediated BAT thermogenesis, although it may have other actions (see below).
SR 59230A has been used as a selective beta-3 adrenoceptor antagonist (13, 14, 20, 45–47, 51, 55), since it was originally introduced (33, 38). Some recent in vitro studies question efficacy and specificity of the beta-3 adrenoceptor antagonist action (8, 23). Some other in vitro studies suggest that SR59230A appears to exhibit competitive antagonist properties on alpha-1 adrenoceptors in isolated artery smooth muscle (5, 7, 29), and to interact with other types of beta-adrenoceptors (6, 8, 25). A major limitation of the drug for long-term recordings in conscious animals is its relatively short duration of action.
Our study focuses on in vivo actions of SR59230A via other subtypes of adrenoceptors on other sympathetically regulated organs and their involvement in producing temperature decreases in conscious intact animals. The high does (10 mg/kg) of SR59230A caused a transient decrease in heart rate and a small fall in skin blood flow. This cardiovascular response may be explained by the possible other receptor potencies of SR59230A (5, 7, 8, 23, 29). Nevertheless, even if SR59230A acts on other adrenoceptors subtypes, as well as beta-3 receptors, it is unlikely that there are major contributions of other sympathetically regulated organs/tissues than BAT to SR59230A-elicited temperature fall. The bradycardia response had ceased by the time the lowest body temperature was achieved. SR59230A caused a small vasoconstriction rather than vasodilatation, indicating no increases in heat dissipation from tail skin. In anesthetized animals, intravenous administration of SR59230A unexpectedly increased basal expiratory CO2 concentration, and in some cases, a small increase in BAT temperature was also observed. On the other hand, in conscious animals, subcutaneous administration of SR59230A caused a substantial decrease in basal BAT temperature. These different responses may reflect complexities in the actions of SR59230A, possibly suggesting an agonist component.
Our present study suggests that ultradian episodic rhythmicity in BAT thermogenesis contributes to the closely associated increases in body and brain temperature. The changes in temperatures, associated with other behavioral and autonomic events, are preceded by increases in hippocampal 5–8 Hz theta rhythm, a marker for arousal and vigilance (40). A reasonable interpretation of such episodic phase-linked events in diverse physiological parameters is that they are dynamic physiological phenomena, rather than homeostatic reflex responses to perturbations in external or internal environments, and thus, they are likely to be driven by brain central command. Ultradian rhythms in brain temperature and wakefulness still appear, perhaps even more prominently after circadian rhythmicity is abolished by destruction of suprachiasmatic nuclei (1, 16). On the other hand, ultradian rhythmicity is greatly diminished in orexin knockout mice (34). Orexin, a hypothalamic neuropeptide, plays an important role in the regulation of sleep/wakefulness, as well as a number of autonomic parameters (39). Thus, the orexin system may play an important role in brain mechanisms coordinating ultradian rhythms.
Perspectives and Significance
Ultradian episodic increases in temperature are often ignored in thermoregulatory studies. Because of intra- and inter-animal differences in the timing of the increases, the ultradian events are not readily apparent in grouped data. In longer-term studies, attention is often focused on circadian rhythms, and in shorter-term studies, attention is usually focused on the temperature response to an experimental manipulation. Nevertheless, ultradian rhythms in body temperature and metabolism have been documented in many species when the animals are left undisturbed under stable environmental conditions (31, 50). In rats, the temporal relationship between temperature and bodily activity has been well documented, with early investigators concluding that metabolic heat produced in skeletal muscle was insufficient to account for the increase in body temperature (24). Thus, as commonly assumed, ultradian temperature increases are not simply due to heat produced as a by-product of general metabolism (obligatory thermogenesis). Clearly, BAT thermogenesis is not the relevant source of heat in all species. Japanese quail, with no BAT, has strong ultradian rhythms in whole body metabolism (49). Since thermogenesis was first ascribed to BAT by Smith and Hock (48), sympathetically regulated BAT metabolism is now recognized to be an important component of overall energy expenditure in homoeothermic animals. In rats, sympathetically controlled thermogenesis in BAT is a well-documented source of facultative heat production initiated by exposure to cold, and most studies of BAT thermogenesis are conducted in a thermoregulatory framework that emphasizes homeostatic correction of temperature deviations from a set point. Ultradian episodic increases in BAT thermogenesis contributing to increases in body and brain temperature do not easily fit into the conventional thermoregulatory framework. We note that within the brain synaptic events are especially temperature sensitive (26), and we suggest that in rats facultative BAT thermogenesis contributes to the episodic increases in brain temperature that facilitate the complex synaptic processes necessary for interaction with the external environment during the ultradian increases in behavioral activity that Kleitman (28) referred to as the basic rest-activity cycle, or BRAC. Active BAT metabolism in normal adult humans (37, 44, 53) may also have functions other than those associated with homeostatic maintenance of “normal” body temperature.
This study was supported by the National Health and Medical Research Foundation of Australia (Grants 426713 and 426716), by Australia Research Council (Grant DP0985144), and by the Flinders Medical Centre Foundation.
No conflicts of interest, financial or otherwise, are declared by the authors.
We thank Robyn Flook, Sarah Todd, Manulua Lomu, and Pam Simpson for their technical assistance.
Present addresses: K. Kulasekara, La Trobe Rural Health School, La Trobe University, P.O. Box 199 Bendigo 3552, VIC, Australia; R. Cunha Alvim de Menezes, Biological Sciences Department, Exact and Biological Sciences Institute, Federal University of Ouro Preto, 354000-000, Ouro Preto, MG, Brazil.
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