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Departments of Psychology (D.L.D., R.J.N.), Neuroscience (R.J.N.), and Biochemistry and Molecular Biology (R.J.N.), Division of Reproductive Biology, The Johns Hopkins University, Baltimore, Maryland 21218-2686; and Center for Behavioral Neuroscience, Department of Biology, Georgia State University (G.E.D.), Atlanta, Georgia 30303
Address all correspondence and requests for reprints to: Randy Nelson, Department of Psychology, 09 Townshend Hall, Ohio State University, Columbus, Ohio 43210. E-mail: rnelson+{at}osu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mounting an immune response requires energy. The cascade of cellular events during the acute phase immune response and inflammation and the elevation of body temperature in response to cytokine activation presumably require substantial energy, although precise quantification is lacking (7, 8). Cytokine activation elevates body temperature, and the energy requirements of inflammation and acute phase immune responses may increase metabolic rates more than 10%/degree of centigrade body temperature elevation (reviewed in Ref. 9). The process of mounting a specific antibody response also appears to require energy. For example, house mice (Mus musculus) injected with a specific antigen, keyhole limpet hemocyanin (KLH), display an increase in both oxygen consumption and metabolic heat production compared with saline-injected controls (10). This result is not specific to small rodents; blue tits (Parus caeruleus) subjected to increased energy turnover have reduced antibody responses, and mounting an antibody response causes an increase in the basal metabolic rate in this avian species (11). In addition, when bumblebees (Bombus terrestris) are challenged with LPS or latex beads that mimic bacteria and activate phagocytosis and access to compensatory food intake is prevented, survival rates are reduced by 50–70% (12). Thus, a general energy deficit can increase the risk of infection and death because insufficient energy reserves may be available to sustain immunity.
The proximate mechanisms by which energy availability is translated into a physiological signal that an animal can use to adjust energy allocation to specific physiological processes remain unspecified. One potential candidate that may act as an endogenous signal of energy availability is the peptide hormone, leptin (Ob protein). Leptin is produced primarily by adipose tissue, and circulating leptin concentrations are positively correlated with the percentage of body fat in a variety of mammals (13, 14). In addition, fasting decreases circulating leptin concentrations (15, 16), and exogenous leptin administration generally reduces food intake (17). Leptin appears to act as a signal mediating physiological functions such as reproduction both directly and indirectly by reflecting energy availability. For example, leptin fully reverses the effects of fasting-delayed puberty in rats restricted to 80% of their ad libitum food intake (18). Exogenous leptin administered during fasting also maintains high LH secretion in ovariectomized adult rats (Rattus norvegicus) (19). Fasting-induced infertility can be reversed in Syrian hamsters (Mesocricetus auratus) through exogenous leptin treatment; this reversal appears to be due to the indirect effects of leptin on metabolic fuel oxidation (20).
Recently, a link has been established between leptin and immune function; mice that are deficient in leptin (ob/ob) or in functional leptin receptors (db/db) are obese and also display impaired T cell immunity despite excessive energy stored as fat (21). Leptin has a specific effect on T lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin also regulates the actions of various cytokines in proinflammatory immune responses (22, 23, 24, 25). Importantly, treatment with leptin counteracts the immunosuppressive effects of starvation (21). Thus, leptin is a likely candidate to mediate the interactions among energy allocation, immune function, and reproduction.
One possible explanation for the observation that leptin replacement counters the immunosuppressive effects of starvation is that the initial decrease in immunity is due to a stress response associated with starvation (21), rather than to reduced energy availability. To address this issue, Siberian hamsters were used in the present study because they are an ideal animal model in which leptin concentrations can be significantly reduced merely through manipulating photoperiod, which does not elicit a stress response. Short-day hamsters consistently reduce body mass (reflected primarily as a decrease in fat) compared with long-day-housed hamsters and therefore display a dramatic reduction in serum leptin concentrations (26). Consistent with the short-day decrease in fat and leptin concentrations, leptin gene expression is reduced in epididymal white adipose tissue (EWAT) and intrascapular brown adipose tissue (IBAT) during winter acclimatization or short photoperiods (27). In addition, leptin receptor gene expression is reduced in the hypothalamic arcuate nucleus in short days (28). Furthermore, maintenance in short days suppresses the ability of Siberian hamsters to mount a specific antibody response (26, 29). The goal of the present study was to examine the role of leptin during photoperiodic changes in immune function in Siberian hamsters. Specifically, if leptin acts as a signal of energy availability, then short-day-housed hamsters should demonstrate reduced body mass, fat mass, leptin concentrations, and humoral immunity. Exogenous leptin administration, however, should counteract the suppression of immune function by providing a false signal of energy availability. Alternatively, if the suppression of immune function in short days is independent of the reduction in leptin, then exogenous leptin should have no effect on immune function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At the onset of the experiment, animals were weighed to the nearest 0.1 g to establish baseline body mass. Twenty of the animals were randomly assigned to 10 weeks of long photoperiod (LD 16:8), and the remaining (n = 20) animals were assigned to 10 weeks of short photoperiod (LD 8:16). Because body mass did not differ among groups at the onset of the experiment, it was assumed that initial leptin concentrations did not differ among groups (26). After 10 weeks, half of the long-day animals (n = 10) and half of the short-day animals (n = 10) were randomly assigned to receive surgically implanted osmotic minipumps (200 µl volume; 0.5 µl/h delivery rate; Alzet 2002, Alza Corp., Mountain View, CA) containing leptin. The rest of the animals received minipumps containing vehicle (0.5 M Tris buffer). Minipumps with leptin contained 2.6 µg/µl leptin (PeproTech, Inc., Rocky Hill, NJ) dissolved in 0.5 M Tris buffer. Minipumps were implanted sc in the intrascapular region of the animals. Animals were allowed to recover from surgery for 3 days before further treatment. After this time, daily food intake was measured to the nearest 0.1 g until the end of the experiment.
After the 3-day recovery period, animals received a single sc injection of 100 µg of the novel antigen KLH suspended in 0.1 ml sterile saline (day 0) and were then returned to the colony room. KLH is an innocuous respiratory protein derived from the giant keyhole limpet (Megathura crenulata). KLH was used because it generates a robust antigenic response in rodents, but does not make the animals ill (e.g. inflammation or fever) (30). This particular assessment was chosen because it was previously reported that generating specific antibodies, including those against KLH, raises oxygen consumption and heat production (10, 11). Blood was drawn from the retroorbital sinus at two different sampling periods (days 5 and 10 postimmunization). These sampling periods were chosen to capture peak IgG production during the course of the immune response to KLH (26). On each sampling day, animals were brought into the surgery room individually and lightly anesthetized with methoxyflurane vapors (Metofane, Medical Developments, Melbourne, Australia), and blood samples (500 µl) were drawn between 1000 and 1200 h Eastern Standard Time. Samples were allowed to clot for 1 h, the clots were removed, and the samples were centrifuged (at 4 C) for 30 min at 2500 rpm. Serum aliquots were aspirated and stored in sealable polypropylene microcentrifuge tubes at -80 C until assayed for IgG. On the last day of sampling (day 10) animals were killed by cervical dislocation. Paired testes, epididymal, inguinal, and retroperitoneal white adipose tissue (EWAT, IWAT, and RWAT, respectively), intrascapular brown adipose tissue (IBAT) (31), and spleens were removed and cleaned of connective tissue at autopsy. All tissue was weighed to the nearest 0.001 g by laboratory assistants blinded to the experimental hypotheses and treatment assignments.
Exp 2
Thirty adult male Siberian hamsters (Phodopus
sungorus; >60 days of age were obtained from the colony at
Georgia State University and handled as described in Exp 1. At the
onset of the experiment, animals were weighed to the nearest 0.1 g
to establish baseline body mass. Ten of the animals were randomly
assigned to 10 weeks of long photoperiod, and the remaining animals
(n = 20) were assigned to 10 weeks of short photoperiod. Body mass
and food intake were measured weekly. After 10 weeks, half of the
short-day animals (n = 10) were randomly selected to receive
surgically implanted osmotic minipumps containing leptin as described
in Exp 1. The rest of the animals received minipumps containing Tris
buffer vehicle. Food intake was controlled in all animals by providing
them with a preset amount of food equal to their mean weekly food
intake immediately before minipump implantation for each animal. This
was done to prevent the increased food intake in short-day
leptin-treated hamsters seen in Exp 1. Three days after minipump
implantation, animals received injections of KLH, and blood samples
(500 µl) were drawn on days 5 and 10 postinjection as described in
Exp 1. Animals were then killed by cervical dislocation, and paired
testes, EWAT, IWAT, RWAT, IBAT, and spleens were removed, cleaned of
connective tissue, and weighed to the nearest 0.001 g.
Humoral immunity
To assess humoral immunity, serum anti-KLH IgG concentrations
were assayed using an enzyme-linked immunosorbant assay. Microtiter
plates were coated with antigen by incubating them overnight at 4 C
with 0.5 mg/ml KLH in sodium bicarbonate buffer (pH 9.6), washed with
PBS (pH 7.4) containing 0.05% Tween 20 (PBS-T; pH 7.4), then blocked
with 5% nonfat dry milk in PBS-T overnight at 4 C to reduce
nonspecific binding and washed again with PBS-T. Thawed serum samples
were diluted 1:20 with PBS-T, and 150 µl of each serum dilution were
added in duplicate to the wells of the antigen-coated plates. Positive
control samples (pooled sera from hamsters previously determined to
have high levels of anti-KLH antibody, similarly diluted with PBS-T)
and negative control samples (pooled sera from KLH-naive hamsters,
similarly diluted with PBS-T) were also added in duplicate to each
plate; plates were sealed, incubated at 37 C for 3 h, then washed
with PBS-T. Secondary antibody (alkaline phosphatase-conjugated
antimouse IgG diluted 1:2000 with PBS-T; Cappel, Durham, NC) was added
to the wells, and the plates were sealed and incubated for 1 h at
37 C. Plates were washed again with PBS-T, and 150 µl of the enzyme
substrate p-nitrophenyl phosphate (Sigma, St.
Louis, MO; 1 mg/ml in diethanolamine substrate buffer) were added to
each well. Plates were protected from light during the enzyme-substrate
reaction, which was terminated after 20 min by adding 50 µl 1.5
M NaOH to each well. The OD of each well was
determined using a plate reader (Benchmark, Bio-Rad Laboratories, Inc., Richmond, CA) equipped with a 405-nm wavelength filter,
and the mean OD for each set of duplicate wells was calculated. To
minimize intraassay variability, the mean OD for each sample was
expressed as a percentage of its plate positive control OD for
statistical analyses.
Leptin RIA
Blood serum leptin concentrations were assayed by RIA using the
Linco Research, Inc. (St. Charles, MO),
125I Multispecies Kit. This assay has been
previously validated for Siberian hamsters (26). The
leptin assay was highly specific, cross-reacting at less than 1% with
other hormones. Serum leptin values were determined in a single RIA.
The coefficients of variation were all less than 10%, and intraassay
variation was less than 2%.
Cortisol RIA
Serum cortisol concentrations were determined by RIA using the
Diagnostics Products (InterMedico, Markham, Canada)
125I double antibody kit. Previous studies have
validated this kit for measuring cortisol in Siberian hamsters, the
primary glucocorticoid in this species (32). The
procedures recommended in the kit were followed, except that half the
volume of all reagents was used, and the volume of standards and
samples was reduced from 25 to 10 µl (32). The cortisol
assay was highly specific, cross-reacting at less than 1% with other
hormones. Serum cortisol values were determined in a single RIA. The
coefficients of variation were all less than 10%.
Statistical analyses
All data for Exp 1 were analyzed using 2 (minipump) x 2
(photoperiod) between-subjects ANOVA. All data for Exp 2 were analyzed
using a one-way ANOVA. All pairwise comparisons of mean differences or
both experiments were conducted using Tukey’s honestly significant
difference post-hoc comparisons. Differences between group
means were considered statistically significant at P <
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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). Short days significantly
reduced body mass in vehicle-treated hamsters (-10.7%;
P < 0.05), but not in leptin-treated hamsters
(P > 0.05; Table 1). Leptin had no effect on body mass
of long- or short-day hamsters (P > 0.05 in both
cases; Table 1). There were no significant interactions of photoperiod
and hormone treatment on testes mass or body mass (P >
0.05 in both cases). Spleen mass was significantly increased in
short-day hamsters (P < 0.05; Table 1). Leptin
treatment had no effect on spleen mass in either photoperiodic
condition (P > 0.05; Table 1).
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). There was a significant interaction
between photoperiod and hormone treatment on IWAT mass
(P < 0.05). RWAT mass was significantly smaller in
short- compared with long-day hamsters (P < 0.05; Fig. 2). Leptin treatment significantly reduced RWAT mass in long days
(P < 0.05), but not in short days (P
> 0.05; Fig. 2). There was a significant interaction of photoperiod
and hormone treatment on RWAT mass (P < 0.05). IBAT
mass was significantly reduced in short days compared with long days
(P < 0.05; Fig. 2). Leptin administration
significantly reduced IBAT mass in short-day hamsters
(P < 0.05), but had no effect on long-day hamsters
(P < 0.05; Fig. 2). There was no interaction of
photoperiod and hormone treatment on IBAT mass (P >
0.05).
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). Leptin treatment significantly
increased food intake in short-day hamsters after both 1 week (4.0%;
data not shown) and 2 weeks (4.2%; P < 0.05 in both
cases; Fig. 3). Leptin treatment did not affect food intake in long-day
hamsters both after 1 week (data not shown) and 2 weeks (Fig. 3) of
leptin treatment (P > 0.05 in both cases). There was a
significant interaction of photoperiod and hormone treatment on food
intake after both 1 and 2 weeks of treatment (P < 0.05
in both cases).
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). Leptin treatment had no effect on IgG
in long-day hamsters (P > 0.05), but in short days,
leptin-treated animals displayed significantly greater IgG than
vehicle-treated animals (P < 0.05; Fig. 4). There was
a significant interaction of photoperiod and hormone treatment on serum
anti-KLH IgG concentrations (P < 0.05).
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). Photoperiodic condition
had no effect on cortisol concentrations (P > 0.05;
Fig. 5). There were no significant interactions between photoperiod and
hormone treatment for spleen mass and cortisol concentrations
(P > 0.05 in both cases).
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).
Short days significantly reduced body mass compared with that in
long-day hamsters (P < 0.05), but leptin-treated
hamsters did not differ from vehicle-treated hamsters in body mass
(P > 0.05; Table 2). EWAT, IWAT, RWAT, and IBAT masses
were significantly reduced in short days compared with long days
(P < 0.05 in all cases); leptin had no effect on any
of the WAT or IBAT pad masses (P > 0.05 in both cases;
Table 2). Spleen mass was significantly increased in short-day
vehicle-treated hamsters compared with long-day animals
(P < 0.05); short-day leptin-treated hamsters did not
differ in spleen mass compared with either short-day vehicle-treated
animals or long-day animals (P > 0.05; Table 2).
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). Leptin treatment had no effect
on anti-KLH IgG concentrations (P > 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In agreement with recent in vitro and in vivo studies (21, 24), the present results demonstrate the immunoenhancing properties of leptin. The present study confirms and extends previous findings that leptin replacement can counteract a reduction in immune function by increasing energy availability (i.e. food intake) (21). In our study, however, the naturalistic reduction in leptin by manipulation of photoperiod was not associated with a stress response. Importantly, photoperiod had no effect on cortisol concentrations in the present study. These results suggest that the actions of reduced leptin on humoral immune function are based on reduced energy stores and not on stress-induced immunosuppression via the HPA axis.
The present results suggest that leptin can act differentially based on the photoperiod to which animals have been exposed (35). In Exp 1, in long-day animals leptin had no effect on the specific antibody response, whereas in short-day animals leptin caused the antibody response to be restored to levels comparable with those in long-day animals. In Exp 2, when the leptin-induced increase in food intake was not permitted in short-day animals, the antibody response remained at the level of short-day control animals. These results suggest that typical long-day leptin concentrations increase energy availability to short-day animals. In short days, body mass and, more specifically, fat mass are greatly reduced, so that exogenous leptin might provide a meaningful signal to an animal that is in a state of reduced energy availability. Basal levels of leptin are already increased in long-day animals (relative to those in short-day animals), potentially preventing exogenous leptin from having any further effects (i.e. a ceiling effect). The lack of an effect of leptin on humoral immunity in long days is not inconsistent with previous studies of leptin and immune function. Studies that have tested the relation between leptin and immune function in vivo have first manipulated endogenous leptin concentrations (e.g. via food restriction) and then replaced the hormone (21). In the present study animals in which leptin administration had no effect on immune function were long-day, vehicle-treated hamsters, in which energy balance remained undisturbed. Thus, leptin treatment appears to restore the reduction in immune function via increased energy availability, rather than by directly enhancing it. It appears that humoral immune function is responsive to energy availability, and restoration of energy availability increases immune function to long-day levels. Taken together, these results suggest that leptin mediates energy allocation to immune function.
The present nonimmune data contrast with the results of two previous studies in hamsters. In one recent study leptin treatment of hamsters reduced body and fat mass to a greater extent in short- compared with long-day animals and reduced food intake similarly in both photoperiods (35). In this study, however, leptin was administered via twice daily injections. In another study that found a decrease in food intake in both long- and short-day hamsters after a single leptin injection, the data were collected at single time point (6 h postinjection) (36). It is possible that these differences in leptin responses are a result of the different methods of administration; the chronic infusion via osmotic minipumps used in the present study might lead to different physiological effects than more acute injections. It is possible that the total amount of leptin administered differed over the course of the studies. One route of administration leads to a bolus of hormone, followed by a drop, and the other results in constant hormone concentrations. Thus, there might be a difference in the sensitivity to leptin according to these different methods. Additionally, in the study that administered twice daily leptin injections (35), when serum leptin was assayed, serum leptin values were lower in leptin-treated hamsters as compared with saline-treated animals in both photoperiods. In the present study the leptin minipumps lead to significantly increased serum leptin values in both photoperiods. It is important to note that the increase in leptin in short days was clearly in the physiological range for long-day animals. Alternatively, it is possible that some of the differences in the response to leptin between previous studies and the present study are due to differences in the photoperiod used. In one of the injection studies (35) a photoperiod of LD 16:8 was used for long days, and LD 10:14 was used for short days. In the present study a photoperiod of 16:8 was used for long days, and 8:16 for long days.
In long-day animals, leptin did not alter food intake, body mass, or white fat (except for RWAT). This is in contrast to the results of other studies in nonseasonal breeders, which suggest that leptin administration leads to a decrease in body mass due to hypophagia (13, 14). It is possible that in seasonally breeding animals such as hamsters, a supraphysiological signal of leptin is ignored; exogenous leptin might only signal to metabolic functions during times of energy crisis. If leptin is an indicator of photoperiodic status, then the addition of leptin when an animal is already in long days might provide only a superfluous signal. There are also species differences with regard to food intake in general between rats and mice, and Siberian hamsters that could account for the differences in leptin effects observed in this species. It is possible that changes caused by leptin administration in Siberian hamsters are reflected in external energy stores (i.e. food caches) rather that in the internal stores, which were indirectly measured in the present study. There are several other cases in which seemingly contradictory effects in Siberian hamsters can be explained by differences in means of energy storage. For example, Siberian hamsters do not increase food intake after a fast, but, rather, they increase food hoarding (37).
Leptin administration increased food intake in short-day-housed hamsters in Exp 1. Leptin administration to animals that are generally considered nonphotoperiodic, such as rats and mice, usually leads to a decrease in food intake (38). Elevated leptin receptor gene expression contributes to an increase in sensitivity to leptin (39). Given that hypothalamic leptin receptor gene expression is reduced in short days (28), it is possible that this reduction might dramatically reduce the sensitivity to leptin in short-day animals. It is also possible that the constant infusion of leptin via minipumps even further down-regulates leptin receptor expression, causing further diminished sensitivity to leptin, potentially leading to the effects on food intake observed in the present study. Reduced receptor expression might also alter leptin negative feedback in short-day animals (28). These potential mechanisms remain to be determined.
The immune function of Siberian hamsters is suppressed in short days in both reproductive responders and nonresponders (26). Importantly, however, leptin concentrations are dramatically reduced in reproductive responders, but are unchanged in nonresponders (26). Given that nonresponders are able to reduce immune function in short days without a decrease in leptin, it appears that nonresponders might be interpreting the leptin signal differently from responders. Presumably, if nonresponders were included in the present study, they would not have enhanced immune function in response to exogenous leptin, because, as in long-day animals, leptin would already be at a high, potentially ceiling concentration, consistent with the results of the present study. We did not test this hypothesis, because all short-day hamsters in the present study were reproductively responsive to photoperiod; future studies are necessary to determine whether nonresponders fail to use leptin as a signal for immune function changes and, if so, what signal might be used that allows nonresponders to show the same degree of immunosuppression as responders. Alternatively, it is possible that nonresponders reduce the number of leptin receptors or reduce the affinity of leptin receptors for circulating leptin, leading to a decreased immune response to the leptin signal.
In the present study photoperiod had no effect on serum cortisol concentrations. This is consistent with data from deer mice, in which photoperiod did not have an effect on circulating corticosterone concentrations (40). In both photoperiods, however, leptin administration resulted in a significant increase in cortisol concentrations. In one previous study central leptin administration leads to a rise in corticosterone secretion at the onset of the dark phase (41). Other studies that show a stimulatory relationship between glucocorticoids and leptin have reported the reverse relationship; glucocorticoids stimulate leptin secretion (42). In many other studies, however, it appears that leptin inhibits glucocorticoid release (43, 44). In contrast to the present study, previous studies did not use seasonally breeding rodents. In general, glucocorticoids have a suppressive effect on immune function (reviewed in Ref. 45). In the present study, however, the leptin-induced enhancement in short days of humoral immune function was accompanied by increased cortisol concentrations. It remains possible that sampling at multiple time points would reveal a difference in the pattern of cortisol secretion observed.
Taken together, the results of the present study suggest that leptin is acting to mediate energy allocation to humoral immune function. When leptin concentrations in reproductive responders are reduced by short photoperiods, immune function is also reduced; exogenous leptin is able to enhance immune function back to the level of long-day animals that have not experienced any loss of leptin. The effects of leptin on immune function in short-day animals appear to be indirect, acting via increased energy availability by increasing food intake. The data indicate that exogenous leptin acts differentially based on photoperiod, because leptin has immune and energetic effects in short, but not in long, days, when leptin concentrations are already high, and energy balance is unperturbed.
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Acknowledgments |
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Footnotes |
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Received September 11, 2000.
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, significantly less than all
other groups (P < 0.05).
