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*HYDROCORTISONE
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Endocrinology Vol. 143, No. 7 2527-2533
Copyright © 2002 by The Endocrine Society

NEUROENDOCRINOLOGY

Melatonin Regulates Energy Balance and Attenuates Fever in Siberian Hamsters

Staci D. Bilbo and Randy J. Nelson

Department of Psychological and Brain Sciences (S.D.B.), The Johns Hopkins University, Baltimore, Maryland 21218-2686; and Departments of Psychology and Neuroscience (R.J.N.), The Ohio State University, Columbus, Ohio 43210-1222

Address all correspondence and requests for reprints to: Staci D. Bilbo, Department of Psychology, The Ohio State University, Columbus, Ohio 43210-1222. E-mail: . bilbo.1{at}osu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Fever is considered an important host defense response but requires significant metabolic energy. During winter many animals must balance immune function with competing physiological demands (i.e. thermoregulation) to survive. Winterlike patterns of melatonin secretion induce a number of energy-saving adaptations. For instance, Siberian hamsters attenuate the duration of fever during simulated short winter day lengths, presumably to conserve energy. To determine the proximate role of melatonin in mediating this photoperiodic response, hamsters housed in long days were injected with saline or melatonin 4 h before lights off for either 1 or 6 wk and assessed for fever following injections of bacterial lipopolysaccharide. Fever duration was attenuated (32%) only in hamsters that decreased body mass, increased cortisol, and exhibited gonadal regression in response to 6 wk of melatonin. Because melatonin-treated hamsters lost significant body mass, fever was assessed in a second long-day group following ad libitum food intake, food restriction, or 24-h food deprivation. Food restriction sufficient to reduce body mass by approximately 25%, but not to reduce leptin, did not influence fever, and 24-h food deprivation virtually abolished fever. Our data suggest that long-term exposure to long-duration melatonin signals is required to induce the physiological changes necessary for short-day immune responses, perhaps involving interactions with hormones such as cortisol and leptin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ACTIVATION OF THE immune system with bacterial lipopolysaccharide (LPS) or the onset of infection results in a stereotypical repertoire of physiological and behavioral responses (1). These responses are ubiquitous among vertebrates and include fever, iron withholding, increased slow-wave sleep, decreased food and water intake, and reduced social interactions (2). Fever is universal among infected animals and reflects a coordinated endocrine, autonomic, and, at times, behavioral response initiated and maintained by the host via endogenous proinflammatory cytokines [e.g. IL-1 (3, 4)]. Rather than being a nonspecific manifestation of illness, fever yields many physiological benefits and is often critical for survival. Most microbial organisms survive and reproduce poorly at elevated temperatures (5), and mammals administered antipyrogenic substances suffer increased mortality from infection (6).

Despite its importance in overcoming infection, mounting an immune response is energetically costly (7, 8, 9). Fever, in particular, entails large metabolic costs; the total increase in metabolism required for each degree Celsius rise in body temperature is estimated to be 10–13% (5). Animals have evolved to maintain a balanced energetic budget. Energy directed toward immune function must be balanced against competing activities such as reproduction, growth, thermoregulation, and cellular maintenance (8). Insufficient food intake generally depresses immune function (9, 10). Mice that are subjected to glucoprivation oxidative stress, which prevents cellular utilization of glucose, are unable to mount normal antibody responses and reduce splenocyte proliferation to a mitogen (8). Similarly, bumblebees (Bombus terrestris) down-regulate immune responses during starvation and allocate energy instead to cardiac and cerebral metabolism, processes vital for immediate survival. Bees that are forced to mount an immune response during starvation suffer increased mortality (9).

Each year a predictable energy shortage arrives during winter when food availability tends to be low and thermoregulatory demands increase. In common with most small mammals, Siberian hamsters cease breeding to conserve energy during the short days of winter. Day length is transduced into a physiological signal by the duration of the nightly secretion of melatonin from the pineal gland (11). Consequently, animals housed in short, winterlike days experience longer nights and longer durations of melatonin than animals housed in long, summerlike days. Hamsters also undergo significant reductions of white adipose tissue and body mass (~25%) during the winter or when housed in short days in the laboratory, despite ad libitum (ad lib) access to food and mild temperatures (12, 13). This strategy presumably evolved because maintenance of a smaller body size throughout winter requires less food and increases thermogenic potential, resulting in daily energetic savings (14).

Seasonal adjustments in immune function may also be critical for winter survival (15). We hypothesized that the onset and expression of fever, because of its highly regulated nature (3), should be plastic according to metabolic demands. We have shown that short days attenuate the acute phase response to LPS in Siberian hamsters by decreasing the production of proinflammatory cytokines and diminishing the durations of fever and anorexia (16). Hamsters appear to use day-length information to orchestrate the response to infection before the onset of challenging environmental conditions. Thus, alterations in energetically costly immune responses during short days may be organized changes in physiology that are mediated via exposure to long-duration melatonin signals. However, because hamsters lose significant body mass during short days, it remains unspecified whether decreases in fever duration simply reflect insufficient metabolic reserves, independent of melatonin. To address this issue, hamsters housed in long days were injected with saline (SAL) or melatonin (MEL) 4 h before lights off for either 1 or 6 wk and assessed for fever following injections of LPS. Six weeks, but not 1 wk, is sufficient time to induce short-day typical gonadal regression and body mass loss (25%). Because melatonin-treated hamsters lost significant body mass, fever was assessed in a second long-day group following ad lib food intake, food restriction, or 24-h food deprivation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Adult (4–5 months of age) male Siberian hamsters (Phodopus sungorus) from our breeding colony were used in this study. All research was conducted with the approval of The Ohio State University Institutional Animal Care and Use Committee, and the treatment of animal subjects was in accordance with the ethical and humane treatment standards of the NIH. All hamsters were individually housed in polypropylene cages (27.8 x 7.5 x 13 cm) in a long-day (LD) photoperiod colony room with a reverse 15:9 light/dark cycle (lights on at 2400 h). Animals were housed with constant temperature and humidity of 21 ± 4 C and 50 ± 10%, respectively, and had constant access to food unless otherwise noted (Harlan Teklad 8640 rodent diet, Indianapolis, IN) and filtered tap water.

Surgical procedures
Hamsters were implanted ip with radiotelemetric transmitters (Mini-Mitter, Sunriver, OR) under sodium pentobarbital anesthesia and allowed to recover for 5 d before subsequent procedures. Cages were placed on TR-3000 receiver boards and connected to DP-24 DataPorts (Mini-Mitter) and a personal computer. Emitted temperature frequencies were collected in 10-min intervals (bins) and were converted to temperature scores by interpolating from programmed calibration curves of individual transmitters. Activity was recorded (10-min bins) as any change in the signal strength from a transmitter and interpreted by the DataPort as an indication that the transmitter moved.

Experiment 1
Melatonin injections.
Thirty-two implanted hamsters were randomly assigned to one of four experimental conditions: 1) eight hamsters received daily sc injections of 0.1 ml 1% ethanol-saline containing 25 µg melatonin (Sigma, St. Louis, MO), according to the protocol of Puchalski and Lynch (17), at 1100 h (4 h before lights off) for 6 wk; 2) eight hamsters received daily sc injections of ethanol-saline vehicle at 1100 h for 6 wk; 3) eight hamsters received daily sc injections of 25 µg melatonin at 1100 h for 1 wk; or 4) eight hamsters received daily sc injections of vehicle for 1 wk.

Fever assessment.
After 1 or 6 wk, all hamsters in each group were lightly anesthetized under isoflurane vapors (Abbott Laboratories, Chicago, IL) at 0900 h, weighed, and had blood (0.25 ml) drawn from the retroorbital sinus into heparinized tubes. Handling was kept consistent and to a minimum (<2 min) and animals were immediately returned to their cages at which time they received their standard injection (SAL or MEL). Blood samples were centrifuged at 3500 rpm for 30 min at 4 C. The supernatant was removed and plasma aliquots frozen at -70 C until assayed for testosterone and cortisol, the primary glucocorticoid in this species (18), by RIA (described below). Hamsters then received a 0.1-ml ip injection of 25 µg LPS (Sigma) suspended in sterile saline just before lights off (1500 h). Activity and body temperature were assessed for the next 18 h. One- and 6-wk groups were run separately. Three naive implanted hamsters received a 0.1-ml ip injection of saline with each group; these animals served as saline-injected controls for the purpose of comparison during fever monitoring.

Control procedures.
Daily injections may be stressful, and chronically elevated cortisol concentrations could alter the interpretation of our results or the onset of fever; thus, 12 previously unmanipulated hamsters were assigned to one of two conditions: six hamsters received daily sc injections of sterile saline at 1100 h for 6 wk, or six hamsters were gently handled daily for 6 wk. At 1 and 6 wk, all animals were lightly anesthetized under isoflurane vapors at 0900 h and blood (0.25 ml) was drawn from the retroorbital sinus into heparinized tubes. Samples were centrifuged, frozen, and later assayed for cortisol concentrations by RIA.

Experiment 2
Food restriction.
Twenty-seven additional implanted hamsters were assigned to one of three groups: 1) nine hamsters were allowed ad lib access to food and water throughout the experiment, 2) nine hamsters were food deprived for 24 h immediately before subsequent procedures, or 3) nine hamsters were gradually food restricted to 75% of ad lib intake over 3 wk until an approximate 25% decrease in body mass was achieved. Baseline ad lib food intake was measured for 15 d before group assignment for subsequent comparison.

Fever assessment.
Following 24-h food deprivation of group 2, all hamsters were lightly anesthetized with isoflurane vapors at 0900 h, weighed, and a blood sample was taken from the retroorbital sinus. Blood was treated as described in experiment 1 until assayed for cortisol and leptin concentrations by RIA. Handling was kept to a minimum (<2 min), and the animals were immediately returned to their cages in the colony room. Hamsters then received a 0.1-ml ip injection of 25 µg LPS in sterile saline just before lights off. Six additional implanted hamsters received a 0.1-ml ip injection of saline. All animals were allowed ad lib access to food and water at this time, and body temperature was assessed for the next 18 h.

RIA procedures
Plasma cortisol concentrations were determined in a single assay for each experiment using a Diagnostic Products Corp. 125I double antibody kit (Los Angeles, CA). Plasma testosterone concentrations were determined in a single assay using a 125I double antibody kit (Diagnostics Systems Laboratories, Inc., Webster, TX). Plasma leptin concentrations were determined in a single assay using the 125I multispecies leptin kit (Linco Research, Inc., St. Charles, MO). These kits have all been previously validated for use in Siberian hamsters (18, 19, 20, 21). Recommended procedures for cortisol and testosterone RIAs were followed exactly except that the volumes of all samples, standards, and reagents were reduced by half. Average assay sensitivities for cortisol, testosterone, and leptin were 10.17 ng/ml, 0.31 ng/ml, and 0.5 ng/ml, respectively. The intraassay coefficients of variation were less than 10% in all cases.

Reproductive and lipid measures
Immediately following the conclusion of all procedures in each experiment, animals were euthanized via rapid cervical dislocation. Paired testes (experiments 1 and 2), epididymal white adipose tissue (EWAT), and brown adipose tissue (experiment 2) were removed, cleaned of connective tissue and fat, and weighed by laboratory assistants unaware of the experimental conditions of the animals.

Statistical analyses
All hormone and body mass data for experiment 1 were analyzed between conditions (SAL vs. MEL) within each group (1 wk vs. 6 wk) using two-tailed t tests. Cortisol concentrations were compared between saline-injected and handled control groups using a two-way repeated measures ANOVA (condition x time). Baseline body temperatures and activity for the active and inactive phases of the light cycle were determined for each animal using mean values for the 2 d before LPS. Body temperatures were analyzed for the 16 h following LPS injections across all time points using repeated measures to assess overall amplitude of fever. We defined fever as temperatures significantly (P < 0.05) higher than active-phase baseline for each 15-min interval using two-tailed t tests. These values were averaged into hours and the total duration (hours) of temperatures above baseline were compared between conditions in each group using two-tailed t tests. Latency to onset of fever was compared using a two-tailed t test. The circadian increase in body temperature (~0.4 C) that occurs 1–2 h before lights out was also analyzed between groups using a two-tailed t test to assess whether SAL vs. MEL animals may increase body temperature according to different circadian timers. Activity (post LPS) was analyzed across each hour by averaging activity counts across 10-min bins and compared with previous baseline between conditions using two-tailed t tests. All data for experiment 2 were analyzed among groups using one-way ANOVAs. Post hoc tests (Tukey’s honestly significant difference) were performed to further distinguish among groups, and all tests were considered statistically significant if P was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1
Six-week group.
Body mass and paired testes mass were significantly reduced following 6 wk of MEL injections, compared with SAL (P < 0.001 for both). Cortisol concentrations were significantly higher in MEL than SAL hamsters (P < 0.03), and testosterone concentrations were undetectable in plasma from MEL-injected hamsters (Fig. 1Go). All animals showed a significant increase in body temperature following injections of LPS, compared with baseline, but overall amplitude of fever was significantly reduced in MEL-injected hamsters (P < 0.001; Fig. 2AGo). The duration (hours) of fever (temperatures significantly higher than active baseline) was also significantly reduced in MEL-injected hamsters (P < 0.01; Fig. 2BGo). Baseline body temperatures, latency to onset of fever, and the circadian increase in body temperature did not differ between groups (data not shown), and control hamsters injected with saline (vs. LPS) did not exhibit fever (Fig. 2AGo). Because we were concerned that MEL-injected animals may be entraining to the time point of the daily injection rather than the onset of darkness, we analyzed activity rhythms before and after LPS. Injections caused a very slight increase in activity in all animals; this increase did not differ between groups (P > 0.05) and quickly returned to baseline until rising again with the onset of darkness (day before LPS). Baseline activity did not differ between groups, and activity was significantly suppressed following injections of LPS, compared with previous baseline in all animals (P < 0.01; data not shown).



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  		Figure 1. Mean (± SEM) body mass (g), paired testes mass (mg), plasma cortisol concentrations (ng/ml), and plasma testosterone concentrations (ng/ml), in hamsters injected with either saline (SAL) (n = 8) or melatonin (MEL) (n = 8) for 6 wk; *, P < 0.05.

 


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  		Figure 2. A, Mean (± SEM) body temperature in 6-wk SAL- and MEL-injected hamsters from 0–16 h post-LPS injections and in control hamsters (n = 3) injected with saline. The black bar indicates the dark phase of the light:dark cycle. Horizontal dashed and dotted lines represent baseline body temperatures for the inactive and active phases, respectively. B, Mean (± SEM) number of hours body temperatures from A were significantly higher than active baseline in 6-wk SAL- and MEL-injected hamsters following LPS injections; *, significantly different from SAL; P < 0.05.

 
One-week group.
Neither body mass nor paired testes mass differed between hamsters receiving SAL or MEL injections for 1 wk (P > 0.05). Cortisol concentrations were significantly higher in MEL animals than in SAL animals (P < 0.001), whereas testosterone concentrations did not differ significantly between groups (Fig. 3Go). Overall amplitude of fever was significantly lower in MEL-injected hamsters than SAL-injected hamsters (P < 0.02; Fig. 4AGo). However, fever duration did not significantly differ between MEL and SAL (P > 0.05; Fig. 4BGo). Baseline body temperatures, latency to onset of fever, and the circadian increase in temperature did not differ between groups (data not shown), and control hamsters injected with saline (vs. LPS) did not display fever (Fig. 4AGo). Baseline activity did not differ between groups, and LPS significantly suppressed activity in both groups (P < 0.05). As in the 6-wk group, activity increased around injections in both conditions but did not differ between conditions (data not shown).



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  		Figure 3. Mean (± SEM) body mass (g), paired testes mass (mg), plasma cortisol concentrations (ng/ml), and plasma testosterone concentrations (ng/ml) in hamsters injected with either SAL (n = 8) or MEL (n = 8) for 1 wk; *, P < 0.05.

 


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  		Figure 4. A, Mean (± SEM) body temperature in 1-wk SAL- and MEL-injected hamsters from 0–16 h post-LPS injections and in control hamsters (n = 3) injected with SAL. The black bar indicates the dark phase of the light:dark cycle. Horizontal dashed and dotted lines represent baseline body temperatures for the inactive and active phases, respectively. B, Mean (± SEM) number of hours body temperatures from A were significantly higher than active baseline in 1-wk SAL- and MEL-injected hamsters following LPS injections.

 
Control injections.
Plasma cortisol concentrations did not differ between daily saline-injected and daily handled control animals after either 1 wk (69.1 ± 6.7 vs. 82.1 ± 8.6 ng/ml) or 6 wk (67.74 ± 8.6 vs. 75.14 ± 8.85 ng/ml) (P > 0.05; data not shown).

Experiment 2
Body mass was significantly reduced in food-restricted hamsters (-26.4%), compared with all other hamsters (P < 0.001). Body mass was also significantly reduced in hamsters food deprived for 24 h (-15%), compared with ad lib hamsters (P < 0.05; Fig. 5Go). Cortisol concentrations were significantly higher in 24-h food-deprived hamsters than ad lib hamsters (P < 0.05; Fig. 5Go). Leptin concentrations, EWAT, and brown adipose tissue masses did not significantly differ among groups (P > 0.05), and paired testes masses were significantly lower in food-deprived and food-restricted hamsters, compared with ad lib animals (P < 0.05; Fig. 5Go). Food deprivation for 24 h almost completely prevented the onset of fever, and significantly reduced fever amplitude and duration, compared with the other groups (P < 0.03, for both; Fig. 6Go). LPS induced fever in both ad lib and food-restricted hamsters, and amplitude, duration, and latency to onset did not differ between groups. Baseline body temperatures did not significantly differ among groups, and saline injections did not cause fever (P > 0.05; Fig. 6AGo).



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  		Figure 5. Mean (± SEM) body mass (g), cortisol concentrations (ng/ml), leptin concentrations (ng/ml), and reproductive organ and fat masses (mg) in ad lib-fed (Ad Lib; n = 9), 24-h food-deprived (FD; n = 9), and food-restricted (FR; n = 9) hamsters before LPS injections. *, Significantly different from Ad Lib group; #, significantly different from FD group; P < 0.05.

 


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  		Figure 6. A, Mean (± SEM) body temperature in ad lib-fed (n = 9), 24-h food-deprived (n = 9), and food-restricted (n = 9) hamsters from 0–16 h post-LPS injections and in control hamsters (n = 6) injected with SAL. The black bar indicates the dark phase of the light:dark cycle. Horizontal dashed and dotted lines represent baseline body temperatures for the inactive and active phases, respectively. B, Mean (± SEM) number of hours body temperatures from A were significantly higher than active baseline; *, significantly different from other groups; P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our data suggest that long-term exposure to short-day durations of melatonin are required to alter the fever response in Siberian hamsters. In experiment 1, fever duration was significantly reduced only in LD hamsters treated with MEL for 6 wk, compared with SAL-treated hamsters. One week of MEL treatment did not reduce fever duration, whereas fever amplitude was slightly attenuated, compared with SAL. Cortisol concentrations were higher in all MEL-injected compared with SAL-injected hamsters. In experiment 2, food restriction sufficient to reduce body mass by approximately 25% did not significantly influence fever, compared with ad lib controls. In contrast, food deprivation for 24 h before LPS elevated cortisol concentrations and almost completely suppressed fever.

Previous research indicated that the duration of fever is reduced in Siberian hamsters housed in short, compared with LDs (16). Fever is energetically expensive, and because hamsters lose significant body mass during short days, we originally hypothesized that decreased metabolic energy availability may lead to reduced fever. Hamsters treated with MEL for 6 wk exhibited decreased testes mass and body mass comparable with that observed in hamsters housed in short days for 8–10 wk (12, 14, 16). However, low body mass alone does not appear to influence fever expression in LD hamsters. Food restriction resulting in approximately 25% reductions in body mass did not influence fever, compared with ad lib controls. In contrast to food restriction, 24-h food deprivation just before LPS almost completely prevented the fever response and significantly delayed its onset. Though unexpected, this result is not unusual. Although this group of animals lost less body mass than the food-restricted group, complete food deprivation represents an extreme physiological stressor, much more so than mild food restriction, and often results in immunosuppression (10, 22). Cortisol concentrations were significantly elevated in 24-h food-deprived animals, compared with ad lib animals, and experimentally stressed animals often do not exhibit fevers in response to LPS (3, 23). However, high cortisol concentrations do not in themselves appear to suppress fever because all MEL-injected hamsters in experiment 1 had increased cortisol without alterations in fever onset.

It was possible that 6-wk MEL-treated hamsters simply entrained their daily activity rhythms to the time of injection at 1100 h rather than to the onset of darkness at 1500 h and thus exhibited reduced fever as an indirect effect of altered activity. However, an analysis of the activity rhythms of MEL- and SAL-treated hamsters in both 1- and 6-wk groups revealed that hamsters restricted activity to the dark phase of the light-dark cycle and that there were no differences in activity between conditions either before or after LPS treatment. Furthermore, the initial onset and amplitude of fever were comparable in all groups, also suggesting that the initiation of an immune response was unaffected by treatment. An additional concern was that the stress of injection itself, either acutely or chronically, may have induced or affected fever; however, control hamsters injected with saline did not exhibit fever, and cortisol concentrations did not differ between SAL-injected and handled control groups at either time point.

Seasonal changes in immune function are widespread (for review see Ref. 15), and increasing evidence suggests that short-day melatonin signals are required to organize changes within the immune system over time (24, 25). The role of melatonin as an immunomodulator is well established, and its direct influence on immune tissue has been elucidated for a variety of species (24, 25, 26, 27, 28, 29, 30, 31). Melatonin attenuates the LPS-induced production of cytokines and prostaglandins in vitro in rats (32, 33) and reduces body temperature in chickens and humans (34, 35) and fever in rats and mice (32, 36). Pharmacological doses of melatonin prevent the in vivo production of cyclooxygenase-2, a central inflammatory mediator involved in the febrile response, in rats with acute inflammation (37). In seasonally breeding animals, centrally acting melatonin is crucial for reproductive involution and appears to mediate several energy-saving behaviors (e.g. nest building, food intake, communal huddling) (25) as well as physiological adjustments (e.g. body mass, metabolic rate, gonadal regression) (38, 39). Our study is the first to suggest that melatonin may organize fever expression in an adaptive and ecologically relevant manner. In agreement with a previous report (40), immune responses appear to follow a similar time course to changes within the reproductive axis, with several weeks of exposure to a given photoperiod necessary to elicit changes. Interestingly, the attenuation of fever amplitude in 1-wk MEL-treated hamsters may reflect preliminary changes in immune function after 1 wk of exposure. Though not statistically significant, testes mass, body mass, and testosterone concentrations in this group appear to be decreasing as well.

Melatonin likely influences fever expression indirectly via interactions with other hormones and cytokines. Leptin, the protein product of the ob gene, is a pleiotropic hormone produced by adipocytes and is suggested to play a significant role in LPS-induced fever (41, 42, 43). Obese Zucker rats with mutations of the leptin receptor (fa/fa) exhibit altered thermogenic capacity, and both increased (44) and decreased (45) fever, compared with lean controls have been reported. Leptin concentrations are correlated to reproductive regression and are decreased several-fold during short days in Siberian hamsters (20). Similarly, gonadal sex steroids exert profound influences on immune function (46, 47) and change dramatically on a seasonal basis in this species. Despite significant decreases in body mass, serum leptin concentrations and EWAT masses did not vary significantly among groups in experiment 2. Testes mass was significantly reduced in food-restricted, compared with ad lib-fed, animals; however, this decrease was small and is no longer significant if corrected for lower body mass (data not shown). Thus, seasonal decreases in leptin in conjunction with reproductive regression may be an important requirement for short-day typical changes in fever expression.

Melatonin, but not saline, injections increased cortisol concentrations in all hamsters. These results are consistent with elevated cortisol concentrations in short-day, compared with LD, Siberian hamsters (48). Contrary to the idea that glucocorticoids necessarily suppress immune function, elevated cortisol concentrations are linked to increases in the absolute number of circulating blood leukocytes and faster inflammatory responses in short-day animals (48). Elevated corticosterone concentrations have also been reported during short days in male prairie voles (Microtus ochrogaster) (49) and white-footed mice (Peromyscus leucopus) (50) and may reflect changes in metabolism. Glucocorticoids mobilize the usage of energy stores throughout the body (51) and may act to allocate appropriate energy stores to immune function. A permissive role for glucocorticoids in the induction of specific immune responses, including fever, has also been described (52). Because 1 wk of MEL did not reduce fever duration, we suggest that cortisol may play a role in organizing the immune response over several weeks of exposure to short days. Importantly, the ability to mount an immune response (i.e. fever onset) was not affected by MEL in the present study. Similarly, hamsters housed in short days for 10 wk exhibit no differences in fever onset, compared with LD hamsters, but rather decrease the duration of fever (16). Taken together, these data strongly suggest that short-day animals have sufficient energy to elicit fever but that the immune response may be more efficient in these animals. In contrast, elevated cortisol in response to food deprivation during long days without the immunoprotective effects of melatonin appears to suppress immune function.

In conclusion, fever in Siberian hamsters fluctuates in response to photoperiod (16), and these changes appear to be organized via melatonin. We suggest melatonin may influence fever via interactions with other hormones such as glucocorticoids, sex steroid hormones, or leptin. The reorganization of energetically costly immune responses throughout the year may enhance survival. Importantly, individual and species variations in the response to infection may represent meaningful, adaptive changes, rather than noxious side effects. A greater understanding of the proximate mechanisms underlying the interaction of environment and the onset of fever may help inform treatment of infection or inflammation.


   Acknowledgments
 
We thank Stephanie Bowers, Brian J. Prendergast, A. Courtney DeVries, and Jim Power for technical assistance, and Tricia Litchfield for expert animal care.


   Footnotes
 
This work was supported by NSF Grant IBN00-08454 and NIH Grant MH-57535.

Abbreviations: ad lib, Ad libitum; EWAT, epididymal white adipose tissue; LD, long day; LPS, lipopolysaccharide; MEL, melatonin; SAL, saline.

Received December 12, 2001.

Accepted for publication April 1, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Berczi I 1998 Neurohormonal host defense in endotoxin shock. Ann NY Acad Sci 840:787–802[CrossRef][Medline]
  2. Hart B 1988 Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123–137[CrossRef][Medline]
  3. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D 1998 Role of fever in disease. Ann NY Acad Sci 856:224–233[CrossRef][Medline]
  4. Saper CB 1998 Neurobiological basis of fever. Ann NY Acad Sci 856:90–94[CrossRef][Medline]
  5. Kluger MJ, Rothenburg BA 1979 Fever and reduced iron: their interaction as a host defense response to bacterial infection. Science 203:374–376[Abstract/Free Full Text]
  6. van Miert AS, van Duin CTH, Busser FJM, Perie N, Ingh TSGAM, Neys-Backers MHHD 1978 The effect of flurbiprofen, a potent non-steroidal anti-inflammatory agent, upon Trypansosoma vivax infection in goats. J Vet Pharmacol Ther 1:69–76[CrossRef]
  7. Ardawi MS, Newsholme EA 1985 Metabolism in lymphocytes and its importance in the immune response. Essays Biochem 21:1–44[Medline]
  8. Demas GE, Chefer V, Talan MI, Nelson RJ 1997 Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/6J mice. Am J Physiol 273:R1631–R1637
  9. Moret Y, Schmid-Hempel P 2000 Survival for immunity: the price of immune system activation for bumblebee workers. Science 290:1166–1168[Abstract/Free Full Text]
  10. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI 1998 Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901[CrossRef][Medline]
  11. Illnerova H, Hoffmann K, Vanecek J 1984 Adjustment of pineal melatonin and N-acetyltransferase rhythms to change from long to short photoperiod in the Djungarian hamster Phodopus sungorus. Neuroendocrinology 38:226–231[Medline]
  12. Bartness TJ, Elliott JA, Goldman BD 1989 Control of torpor and body weight patterns by a seasonal timer in Siberian hamsters. Am J Physiol 257:R142–R149
  13. Knopper LD, Boily P 2000 The energy budget of captive Siberian hamsters, Phodopus sungorus, exposed to photoperiod changes: mass loss is caused by a voluntary decrease in food intake. Physiol Biochem Zool 73:517–522[CrossRef][Medline]
  14. Steinlechner S, Heldmaier G 1982 Role of photoperiod and melatonin in seasonal acclimatization of the Djungarian hamster, Phodopus sungorus. Int J Biometeorol 26:329–337[CrossRef][Medline]
  15. Nelson RJ, Demas GE 1996 Seasonal changes in immune function. Q Rev Biol 71:511–548[CrossRef][Medline]
  16. Bilbo SD, Drazen DL, Quan N, He L, Nelson RJ 2002 Short day lengths attenuate the symptoms of infection in Siberian hamsters. Proc R Soc Lond B Biol Sci 269:447–454[Medline]
  17. Puchalski W, Lynch GR 1988 Daily melatonin injections affect the expression of circadian rhythmicity in Djungarian hamsters kept under a long-day photoperiod. Neuroendocrinology 48:280–286[CrossRef][Medline]
  18. Reburn CJ, Wynne-Edwards KE 1999 Hormonal changes in males of a naturally biparental and a uniparental mammal. Horm Behav 35:163–176[CrossRef][Medline]
  19. Jasnow AM, Huhman KL, Bartness TJ, Demas GE 2000 Short-day increases in aggression are inversely related to circulating testosterone concentrations in male Siberian hamsters (Phodopus sungorus). Horm Behav 38:102–110[CrossRef][Medline]
  20. Drazen DL, Kriegsfeld LJ, Schneider JE, Nelson RJ 2000 Leptin, but not immune function, is linked to reproductive responsiveness to photoperiod. Am J Physiol 278:R1401–R1407
  21. Drazen DL, Demas GE, Nelson RJ 2001 Leptin effects on immune function and energy balance are photoperiod dependent in Siberian hamsters (Phodopus sungorus). Endocrinology 142:2768–2775[Abstract/Free Full Text]
  22. Simons CT, Kulchitsky VA, Sugimoto N, Homer LD, Szekely M, Romanovsky AA 1998 Signaling the brain in systemic inflammation: which vagal branch is involved in fever genesis? Am J Physiol 275:R63–R68
  23. Johnson RW, Propes MJ, Shavit Y 1996 Corticosterone modulates behavioral and metabolic effects of lipopolysaccharide. Am J Physiol 270:R192–R198
  24. Nelson RJ, Demas GE 1997 Role of melatonin in mediating seasonal energetic and immunologic adaptations. Brain Res Bull 44:423–430[CrossRef][Medline]
  25. Nelson RJ, Drazen DL 1999 Melatonin mediates seasonal adjustments in immune function. Reprod Nutr Dev 39:383–398
  26. Maestroni GJ 1993 The immunoneuroendocrine role of melatonin. J Pineal Res 14:1–10[Medline]
  27. Liebmann PM, Wolfler A, Felsner P, Hofer D, Schauenstein K 1997 Melatonin and the immune system. Int Arch Allergy Immunol 112:203–211[Medline]
  28. Conti A, Maestroni GJM, McCann SM, Sternberg EM, Lipton JM, Smith CC, eds. 2000 Neuroimmunomodulation. Perspectives at the new millennium. New York: Annals of the New York Academy of Science
  29. Demas GE, Nelson RJ 1998 Exogenous melatonin enhances cell-mediated, but not humoral, immune function in adult male deer mice (Peromyscus maniculatus). J Biol Rhythms 13:245–252[Abstract]
  30. Drazen DL, Klein SL, Yellon SM, Nelson RJ 2000 In vitro melatonin treatment enhances splenocyte proliferation in prairie voles. J Pineal Res 28:34–40[CrossRef][Medline]
  31. Drazen DL, Bilu D, Bilbo SD, Nelson RJ 2001 In vitro melatonin enhancement of splenocyte proliferation is attenuated in mice by luzindole, a melatonin receptor antagonist. Am J Physiol 280:1476–1482
  32. Nava F, Calapai G, Facciola G, Cuzzocrea S, Giuliani G, De Sarro A, Caputi AP 1997 Melatonin effects on inhibition of thirst and fever induced by lipopolysaccharide in rat. Eur J Pharmacol 331:267–274[CrossRef][Medline]
  33. Sacco S, Aquilini L, Ghezzi P, Pinza M, Guglielmotti A 1998 Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro. Eur J Pharmacol 343:249–255[CrossRef][Medline]
  34. Rozenboim I, Miara L, Wolfenson D 1998 The thermoregulatory mechanism of melatonin-induced hypothermia in chicken. Am J Physiol 274:R232–R236
  35. Deacon S, Arendt J 1995 Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans. Brain Res 688:77–85[CrossRef][Medline]
  36. Raghavendra V, Agrewala JN, Kulkarni SK 2000 Melatonin reversal of lipopolysaccharide-induced thermal and behavioral hyperalgesia in mice. Eur J Pharmacol 395:15–21[CrossRef][Medline]
  37. Cuzzocrea S, Costantino G, Mazzon E, Caputi AP 1999 Regulation of prostaglandin production in carrageenan-induced pleurisy by melatonin. J Pineal Res 27:9–14[Medline]
  38. Heldmaier G, Steinlechner S, Ruf T, Wiesinger H, Klingenspor M 1989 Photoperiod and thermoregulation in vertebrates: body temperature rhythms and thermogenic acclimation. J Biol Rhythms 4:251–265
  39. Heldmaier G, Ruf T 1992 Body temperature and metabolic rate during natural hypothermia in endotherms. J Comp Physiol [B] 162:696–706[CrossRef][Medline]
  40. Prendergast BJ, Nelson RJ 2001 Spontaneous "regression" of enhanced immune function in a photoperiodic rodent Peromyscus maniculatus. Proc R Soc Lond B Biol Sci 268:2221–2228[Medline]
  41. Ivanov AI, Romanovsky AA 2002 Fever responses of Zucker rats with and without fatty mutation of the leptin receptor. Am J Physiol 282:R311–R316
  42. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS 1998 Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1:445–450[CrossRef][Medline]
  43. Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ 1999 Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl Acad Sci USA 96:7047–7052[Abstract/Free Full Text]
  44. Plata-Salaman CR, Peloso E, Satinoff E 1998 Cytokine-induced fever in obese (fa/fa) and lean (Fa/Fa) Zucker rats. Am J Physiol 275:R1353–R1357
  45. Zeisberger E, Roth J, Storr B, Rosenthal M 1997 Fever and stress in lean and obese Zucker rats. Ann NY Acad Sci 813:401–412[Medline]
  46. Bilbo SD, Nelson RJ 2001 Sex steroid hormones enhance immune function in male and female Siberian hamsters. Am J Physiol 280:R207–R213
  47. Klein SL 2000 The effects of hormones on sex differences in infection: from genes to behavior. Neurosci Biobehav Rev 24:627–638[CrossRef][Medline]
  48. Bilbo SD, Dhabhar FS, Viswanathan K, Saul A, Yellon SM, Nelson RJ 2002 Short day lengths augment stress-induced leukocyte trafficking and stress-induced enhancement of skin immune function. Proc Natl Acad Sci USA 99:4067–4072[Abstract/Free Full Text]
  49. Nelson RJ, Fine JB, Demas GE, Moffatt CA 1996 Photoperiod and population density interact to affect reproductive and immune function in male prairie voles. Am J Physiol 270:R571–R577
  50. Ransone Jr SN, Bradley EL 1992 Correlations between serum corticosterone concentration and reproductive conditions in the white-footed mouse (Peromyscus leucopus noveboracensis). Comp Biochem Physiol C 102:453–457[CrossRef]
  51. Turnbull A, Rivier C 1999 Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 79:1–71[Abstract/Free Full Text]
  52. Ben-Hur T, Cialic R, Itzik A, Barak O, Yirmiya R, Weidenfeld J 2001 A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis. Neuroscience 108:119–127[CrossRef][Medline]



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