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1 Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Department of Medicine and the Tupper Research Institute, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111; and 2 Department of Chemistry, University of Arizona, Tucson, Arizona 85721
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ABSTRACT |
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 Top
 Abstract
 Introduction
METHODS
Results
Discussion
References
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Inflammation and microbial infection
produce symptoms, including fever, anorexia, and hypoactivity, that are
thought to be mediated by endogenous proinflammatory cytokines.
Melanocortins are known to act centrally to suppress effects on fever
and other sequelae of proinflammatory cytokine actions in the central
nervous system, but the roles of melanocortins in anorexia and
hypoactivity occurring during the acute phase response are unknown. The
present study was designed to determine the effects of exogenous and
endogenous 
-melanocyte stimulating hormone (-MSH) on
lipopolysaccharide (LPS)-induced anorexia in relation to their effects
on fever. Rats were fasted overnight to promote feeding behavior, then
injected intraperitoneally with LPS (100 µg/kg ip), followed 30 min
later by intracerebroventricular injection of either
-MSH or the melanocortin receptor subtype 3/subtype 4 (MC3-R/MC4-R)
antagonist SHU-9119. Food intake, locomotor activity, and body
temperature (Tb) were monitored
during the ensuing 24-h period. Each of two intracerebroventricular doses of -MSH (30 and 300 ng) potentiated the suppressive effects of
LPS on food intake and locomotion, despite the fact that the higher
dose alleviated LPS-induced fever. In control rats that were not
treated with LPS, only the higher dose of -MSH significantly inhibited food intake, and Tb and
locomotor activity were unaffected. To assess the roles of endogenous
central melanocortins, LPS-treated rats received
intracerebroventricular SHU-9119 (200 ng). Central MC3-R/MC4-R blockade
did not affect Tb or food intake
in the absence of LPS treatment, but it reversed the LPS-induced
reduction in 24-h food intake and increased LPS-induced fever without
altering the LPS-induced suppression of locomotion. Taken together, the results suggest that exogenous and endogenous melanocortins acting centrally exert divergent influences on different aspects of the acute
phase response, suppressing LPS-induced fever but contributing to
LPS-induced anorexia and hypoactivity.
lipopolysaccharide; -melanocyte stimulating hormone; melanocortin receptor; rat; SHU-9119
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INTRODUCTION |
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Top
Abstract
Introduction
METHODS
Results
Discussion
References
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FEVER, ANOREXIA, and reduced physical activity are
classic features of the coordinated host response to microbial
infection and chronic inflammatory diseases, which are generally
believed to be mediated by host-derived proinflammatory cytokines
acting on the central nervous system (CNS; 4, 22). Melanocortins, or -melanocyte stimulating hormones (MSH) and ACTH-related peptides, are pleiotropic functional antagonists of many central actions of
proinflammatory cytokines and endotoxin (2, 11, 24). Exogenous -MSH
administered centrally or peripherally suppresses lipopolysaccharide
(LPS)- and interleukin (IL)-1-induced fever (2, 11, 12) and activation
of the hypothalamic-pituitary-adrenal axis (12, 25, 29). Furthermore,
during fever endogenous melanocortins are active centrally, exerting an
antipyretic influence by acting on melanocortin receptors (MCR) within
the CNS (11).
In addition to these antipyretic and anti-inflammatory effects, the roles of endogenous melanocortins in the normal control of appetite and energy balance have recently been the focus of intense interest. Exogenous melanocortins suppress food intake (6, 19, 23, 33), whereas disruption of melanocortin signaling either by targeted ablation of the CNS-associated MCR subtype 4 (MC4-R) (13) or overexpression of the endogenous MCR antagonist proteins agouti and agouti-related protein, produces hyperphagia and profound obesity in mice (21, 36). Furthermore, central administration of the MCR subtype 3 (MC3-R)/MC4-R antagonist SHU-9119 inhibits leptin-induced anorexia (28). These findings strongly support a physiological inhibitory role of central melanocortins in the normal control of appetite, wherein hypothalamic melanocortinergic neurons may function as transducers of central satiety-inducing signals.
These recent insights provide a plausible basis for two alternative, contradictory hypotheses concerning the potential central roles of melanocortins in infection-associated anorexia. On the one hand, on the basis of the anorexic properties of melanocortins in normal animals, one would predict that melanocortins may contribute to, or exacerbate, illness-induced anorexia. On the other hand, LPS-induced proinflammatory cytokines [tumor necrosis factor (TNF), IL-1, IL-6, IL-8] that have been implicated in anorexia are also pyrogenic (4, 15, 22, 30), whereas antipyretic agents including indomethacin reportedly suppress the anorexic action of IL-1 (31, 34). Therefore, considering the antipyretic and other pleiotropic proinflammatory cytokine-suppressing actions of melanocortins, it might be predicted that melanocortins would tend to suppress endotoxin-induced anorexia and hypoactivity.
To test these alternative hypotheses, the present study used an animal
model that exerts conflicting influences on food intake: an overnight
fast followed by systemic LPS treatment. The effects of central
administration of -MSH and of central MCR blockade were then
determined to assess the influence of exogenous and endogenous
melanocortins on LPS-induced fever, anorexia, and locomotion over a
24-h period. The results indicate that, despite the suppressive influence of exogenous and endogenous central melanocortins on LPS-induced fever, centrally administered melanocortins exacerbate LPS-induced anorexia and hypoactivity, and centrally acting endogenous melanocortins are involved in mediating LPS-induced anorexia.
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METHODS |
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Top
Abstract
Introduction
METHODS
Results
Discussion
References
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Animals and Surgical Procedures
Adult male Sprague-Dawley rats (Taconic, Germanton, NY) initially weighing 270-300 g were used. The rats were initially housed in group cages (3 per cage) in a room with temperature controlled at 21 ± 1°C and a 12:12-h light-dark cycle (lights on at 0600). Standard rodent chow (PROLAB 3000, Agway, Syracuse, NY) and tap water were provided ad libitum throughout the experiments, except where indicated. All procedures were approved by the Animal Research Committee of Tufts University Medical School and New England Medical Center.A week before the experiments, under pentobarbital sodium anesthesia (50 mg/kg ip), each rat was implanted intraperitoneally with a battery-operated radiotelemetry transmitter (Mini-Mitter, Sunriver, OR) for monitoring body temperature (Tb) and motor activity and an intracerebroventricular 22-gauge stainless steel guide cannula (Plastics One, VA) in the right lateral ventricle for intracerebroventricular injections as described previously (11). After surgery, the rats were placed in individual cages and housed in a separate room with temperature controlled at 25 ± 1°C, in or near the thermoneutral ambient temperature range for rats. Correct placement of intracerebroventricular cannulas was verified by injection of 10 µl of 0.1% cresyl violet through the guide cannula at the end of the experiment followed by postmortem brain dissection. Data obtained from rats with misplaced cannulas were excluded from analysis.
Animal Handling and Intracerebroventricular Injections
Each rat was used in only one experiment. To minimize the potential influence of nonspecific stress on results, each rat was conditioned daily to gentle handling for 5 consecutive days before experiments, including a simulated intracerebroventricular injection performed by removing the dummy cannula and connecting the injection device to the intracerebroventricular guide cannula. Intracerebroventricular injections were delivered at a speed of 2 µl/ min using a 100 µl Hamilton syringe driven by a microinfusion pump (Bee, MF-9090, Bioanalytic Systems, West Lafayette, IN) as described earlier (11). Injection cannulas were left in place for 2 min after infusion to prevent any injectate reflux.Tb and Locomotion Measurement
Tb of rats was monitored continuously via a receiver placed under each cage. Emitted frequencies were transmitted into a peripheral processor (Mini-Mitter) connected to a personal computer, recorded at 10-min intervals, and converted into Tb values according to the frequency-temperature calibration curves, using the Vitalview software package (Mini-Mitter). Each transmitter was calibrated before experiments according to the manufacturer's instructions. Gross locomotor activity was also measured using the Mini-Mitter system, as described previously (16). In this system, activity is detected as changes in the angular changes in transmitter position and recorded as motor activity counts.Experimental Protocol
One day before experiments, rats were weighed and assigned arbitrarily to body weight-matched groups. Tb and motor activity of the rats were recorded at 10-min intervals starting at 0900. The rats were deprived of food at 1600, but free access to tap water was provided. Between 0900 and 1000 on the following day (designated day 1), rats were injected intraperitoneally with either saline (0.9% sterile NaCl) or LPS (100 µg/kg, in 200 µl saline), followed 30 min later by intracerebroventricular injection with either saline or one of two doses of-MSH [30 or 300 ng (200 pmol) in 6 µl of
saline] or SHU-9119 [200 ng (168 pmol) in 4 µl of
saline] as indicated below. Immediately after intraperitoneal LPS
or saline treatment, preweighed rat chow pellets were placed in the
chow bin for free access by the rats. Food consumption was measured at
2, 4, 6, 8, and 24 h after intraperitoneal saline or LPS by weighing
the remaining food pellets along with any spillage into the cage.
Recording of Tb and motor activity
was terminated at 1100 on day
2.
Drugs
SHU-9119 was prepared by Dr. Wei Yuan as described earlier (10). Stock solutions of LPS derived from Escherichia coli endotoxin (0111:B4, Sigma),-MSH (Peninsula
Laboratories, Belmont, CA), and SHU-9119 were prepared by dissolving in
sterile saline containing 0.1% low endotoxin BSA at a concentration of
1 mg/ml and freezing in aliquots at 
70°C. Immediately before
experiments, fresh aliquots of the respective stock solutions were
thawed and further diluted with saline to the respective injectate concentrations.
Data Analysis and Statistics
Average Tb values for 30-min periods were computed from Tb recorded at 10-min intervals. For each rat, Tb was expressed as change from a baseline value that was computed as the mean Tb during the 4-h period between 0600 and 1000 on day 1. To account for differences in feeding behavior, motor activity, and Tb associated with the photoperiod, the 24-h Tb data were accordingly divided into three periods for statistical analysis [0-8 h (lights on), 9-20 h (lights off), and 21-24 h (lights on)]. Integrated Tb responses [areas under the curves (AUC)] in each period of time were calculated using the trapezoidal method as described earlier (11). Motor activity for 30-min intervals was computed from the primary 10-min activity counts recorded by the telemetry system. The data were arbitrarily divided into three time blocks as described for Tb data. Hourly means of the motor activity counts during each time period were used for statistical analysis and computation of group means. For food intake, cumulative individual food intake at the indicated time intervals was used for statistical analysis and computation of group means. Treatment-associated group differences for Tb AUC data, food intake, and locomotor activity were analyzed by one-way ANOVA followed by Scheffé's test. Differences were considered statistically significant at values of P < 0.05.| |
RESULTS |
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Top
Abstract
Introduction
METHODS
Results
Discussion
References
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Effects of Intracerebroventricular Injection of -MSH on
Food Intake, Tb, and Motor Activity in
LPS-Treated Rats
-MSH at doses of both 30 and 300 ng delivered 30 min after LPS injection potentiated LPS-induced reduction in food
intake during the 0- to 2-, 0- to 4-, and 0- to 6-h time periods
(Fig. 1). Effects of the two -MSH doses tested (30 and 300 ng) were similar. During the periods 0-8 and 0-24 h after LPS, the cumulative food intake in the -MSH-treated rats remained decreased in comparison with that in rats not receiving -MSH, but
the effects failed to reach statistical significance
(P = 0.25) (Fig. 1).
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Tb. As expected,
intraperitoneal injection of LPS resulted in a marked rise in
Tb, which peaked 6-8 h after
its injection and lasted >24 h. Intracerebroventricular injection of
30 ng -MSH after LPS had no effect on LPS-induced fever (Fig.
2). In contrast, intracerebroventricular
administration of 300 ng -MSH significantly suppressed LPS-induced
fever 0-8 h after LPS injection, completely preventing the onset
of fever for at least 3 h (Fig. 2). During the period corresponding to
the dark phase (9-20 h after LPS injection), the mean
Tb in rats receiving LPS plus
intracerebroventricular -MSH (300 ng) remained lower than that in
the rats treated with LPS plus intracerebroventricular saline (Fig.
2A), but the effect was no longer
statistically significant by comparison of
Tb AUC data (Fig.
2B). Control rats receiving
intraperitoneal and intracerebroventricular saline treatments exhibited
only a negligible rise in Tb of
<0.5°C throughout most of the 24-h measurement period (Fig.
2A).
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Locomotor activity. Baseline locomotor
activities were similar in all treatment groups (Fig.
3A).
During the light phase (0-8 h after LPS treatment), the locomotor
activity in LPS-treated rats was slightly, but not significantly, lower
than that in intraperitoneal saline-treated controls (Fig.
3B). Both intracerebroventricular doses of -MSH produced somewhat greater decreases in motor activity that were statistically significant compared with those of controls (Fig. 3). During the dark phase (9-20 h after LPS injection), all
LPS-treated groups exhibited marked and significant reductions in
locomotor activity compared with control rats receiving intraperitoneal and intracerebroventricular saline (Fig. 3). Intracerebroventricular injection of 300 ng, but not 30 ng, of -MSH significantly
potentiated the LPS-induced suppression of locomotion during this
period (Fig. 3). During the period 21-24 h after intraperitoneal
LPS, corresponding to the beginning of the light phase of
day
2, locomotor activity remained lower
in rats treated with LPS plus intracerebroventricular -MSH than
those in rats treated either with intraperitoneal LPS plus
intracerebroventricular saline or with
intraperitoneal/intracerebroventricular saline controls (effect was
statistically significant for 300 ng but not for 30 ng -MSH) (Fig.
3).
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Effects of Central MCR Blockade by Intracerebroventricular SHU-9119 on Food Intake, Tb, and Locomotor Activity in LPS-Treated Rats
Food intake. To assess whether endogenous central melanocortins are involved in mediating LPS-induced anorexia, we tested the effect of intracerebroventricular injection of the MC3-R/MC4-R antagonist SHU-9119 on food intake in fasted, LPS-treated rats. Intracerebroventricular SHU-9119 significantly inhibited the LPS-induced suppression of cumulative food intake during the 0- to 24-h post-LPS interval (P < 0.05); food intake during this period in rats treated with LPS plus intracerebroventricular SHU-9119 was not significantly different from that in control rats not treated with LPS (Fig. 4). The anti-anorexic effect of intracerebroventricular SHU-9119 appeared as a progressive trend beginning in the 0- to 6- and 0- to 8-h post-LPS intervals, but reached statistical significance only during the 0- to 24-h interval. In control rats receiving intraperitoneal saline rather than LPS, intracerebroventricular SHU-9119 had no effect on food intake (Fig. 4).
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Tb. Consistent
with our previous results (11), intracerebroventricular injection of
SHU-9119 (200 ng) exacerbated LPS-induced fever during the period
0-8 h after LPS, but not during subsequent intervals (Fig.
5). Intracerebroventricular administration
of SHU-9119 alone had no significant effect on
Tb in control rats receiving
intraperitoneal saline rather than LPS (Fig. 5).
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Locomotor activity. LPS treatment
suppressed locomotor activity only slightly during the period 0-8
h post-LPS but dramatically reduced motor activity during the dark
phase (9-20 h post-LPS) (P < 0.01) (Fig. 6). Intracerebroventricular
SHU-9119 had no effect on the LPS-induced suppression of locomotor
activity (Fig. 6). Furthermore, in the absence of LPS treatment,
intracerebroventricular SHU-9119 had no effect on locomotor activity
compared with that in controls receiving
intraperitoneal/intracerebroventricular saline (Fig. 6).
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Effects of Intracerebroventricular Injection of -MSH
on Food Intake, Tb, and Locomotor
Activity in Normal Rats
-MSH significantly reduced cumulative food intake during the 0- to 4-, 0- to 6-, and 0- to
8-h postinjection intervals (P < 0.05 for each interval), but not during the 0- to 24-h interval.
Comparable intracerebroventricular injection of 30 ng -MSH had no
effect on food intake (Fig. 7). Neither
intracerebroventricular dose of -MSH affected
Tb or locomotor activity
significantly in these rats (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
METHODS
Results
Discussion
References
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The principal finding of this study concerns the divergent roles of
melanocortins in regulating different components of the LPS-induced
acute phase response. The anorexic effect of LPS was potentiated by
exogenous intracerebroventricular -MSH and was reversed by central
MCR blockade, indicating that centrally acting endogenous melanocortins
may be involved in mediating LPS-induced anorexia. Exogenous
intracerebroventricular -MSH also exacerbated LPS-induced
hypoactivity. In contrast, exogenous and endogenous melanocortins were
shown to alleviate LPS-induced fever in the same experiments,
consistent with previous findings (2, 11, 12).
The observations that exogenous -MSH potentiated and that central
MCR blockade reversed LPS-induced anorexia are consistent with the
compelling array of evidence supporting a suppressive role of central
melanocortins in the normal regulation of food intake (6, 13, 36).
Nevertheless, in the present studies, the effects of
intracerebroventricular -MSH (agonist) and SHU-9119 (antagonist) on
LPS-induced anorexia were qualitatively distinct from those seen in
control fasted rats. First, the potentiating effect of exogenous
-MSH on anorexia in fasted, LPS-treated rats was exhibited more
rapidly and at a lower dose than -MSH-induced inhibition of food
intake in the control fasted rats (0- to 2- vs. 0- to 4-h interval; 30 ng vs. 300 ng, respectively) (Figs. 1 and 7). Second, the dose of
SHU-9119 used in this study reversed the LPS-induced suppression of
food intake in fasted rats during the 0- to 24-h post-LPS interval, but
had no effect by itself in similarly fasted control rats. These
differences between LPS-treated and untreated rats are indicative of
increased responsiveness to the anorexic action of -MSH and an
apparent enhancement of the anorexic role of endogenous melanocortins
during the LPS-induced inflammatory state. Similarly, the suppressive
effects of -MSH on Tb and
locomotion also appeared to be state dependent, because they were not
observed in control fasted rats. The mechanisms involved in these
state-dependent changes in -MSH responsiveness are unknown, but the
phenomenon of LPS-induced responsiveness to the
Tb-lowering action of -MSH is
highly consistent with previous results (2, 11, 12).
The factors involved in mediating LPS-induced anorexia are poorly
understood. Although LPS-induced cytokines, including TNF-, IL-1
,
and IL-6, are known to induce anorexia (4, 22, 26, 30), none of these
cytokines has been proven to be essential for LPS-induced anorexia. For
instance, anorexic responses to LPS persist in IL-1-deficient,
IL-6-deficient, and TNF- double receptor-knockout mice (7, 8, 18).
Other studies suggested a role of leptin in mediating LPS-induced
anorexia. Leptin is a cytokine produced by white adipocytes that is
thought to participate in the normal feeding- and fasting-induced
regulation of appetite and energy disposition. Fasting suppresses
leptin secretion, whereas treatment of fasted rodents with LPS or
proinflammatory cytokines increased leptin gene expression and plasma
leptin levels (9, 26). However, as was found in the case of
proinflammatory cytokines, leptin signaling is not an absolute
requirement for LPS-induced anorexia, because leptin-deficient
ob/ob mice and leptin
receptor-deficient db/db mice do
exhibit LPS-induced anorexia, although the
db/db mice exhibit partial resistance
to the effect (5). Available evidence thus suggests that multiple
cytokines are probably involved in mediating LPS-induced anorexia, and
the long-term absence of a given cytokine or cytokine receptor can
elicit effective compensatory responses that preserve the
illness-associated anorexic response.
The roles of endogenous melanocortins in modulating LPS-induced febrile
and anorexic responses appear to be temporally distinguishable. Intracerebroventricular SHU-9119 treatment reversed the LPS-induced anorexia that occurred during the full 24-h post-LPS period, but it had
no apparent effect on LPS-induced anorexia during the first several
hours after LPS. In contrast, this treatment exacerbated LPS-induced
fever during the first several hours post-LPS (Fig. 5), and in our
previous study the same treatment produced a blockade of the
antipyretic effect of exogenous intracerebroventricular -MSH that
was virtually immediate (11). Therefore, endogenous melanocortins
appear to be involved in mediating the later phase of LPS-induced
anorexia, but not the earlier phase of anorexia occurring during the
first few hours after LPS treatment. In this connection,
intracerebroventricular treatment with SHU-9119 blocked leptin-induced
anorexia in rats during the first 4 h after leptin administration (27,
28), implicating a role of central melanocortin receptors in mediating
the acute anorexic effects of leptin. Leptin secretion gradually
increases after cytokine administration in fasted mice, peaking at 7 and 10 h, respectively, after TNF- and IL-1 injection (26).
Therefore, one potential sequence of events that theoretically could
account for the contribution of endogenous melanocortins to the later
phase of LPS-induced anorexia is the following: LPS-induced release of
proinflammatory cytokines, which then stimulate release of leptin (9,
26), which may then activate proopiomelanocortin neurons to release
central melanocortins that suppress feeding by acting via the MC4-R
and/or MC3-R (27, 28). Further studies would be needed to test
this hypothesis.
The effects of melanocortins on LPS-induced suppression of feeding
behavior have not previously been reported. However, in one relevant
study, it was reported that the anorexia resulting from central
injection of IL-1 in rats was inhibited by intracerebroventricular administration of -MSH (35). The present results do not necessarily conflict with those findings, because the mechanisms of LPS-induced and
IL-1-induced anorexia are clearly distinct, as indicated by several
lines of evidence from previous studies. First, IL-1 appeared not to be
involved in LPS-induced anorexia, because intracerebroventricular injection of IL-1 receptor antagonist failed to inhibit LPS-induced anorexia, whereas it did prevent the anorexia induced by
intracerebroventricular or intraperitoneal IL-1 (14). Second,
IL-1-deficient mice exhibited LPS-induced anorexia (16). Third, the
anorexic effects of IL-1 and LPS are qualitatively different,
because the anorexic effect of LPS was attributable to reduction of
meal frequency, whereas the anorexic response to IL-1 resulted
primarily from reduced meal size (17). Therefore, the differential
effects of intracerebroventricular -MSH on the anorexic states
induced by intraperitoneal LPS (present study) and
intracerebroventricular IL-1 (35) are not surprising.
Another question addressed by the present study is whether LPS-induced
anorexia is dependent on the febrile state. Because intracerebroventricular -MSH potentiated LPS-induced anorexia while
simultaneously suppressing fever, the results indicate that LPS-induced
anorexia is not secondary to the LPS-induced fever. These results are
thus consistent with those in the earlier study of McCarthy et al.
(20), which showed that LPS-induced anorexia persisted in rats despite
suppression of the accompanying fever by salicylate.
The present studies also revealed that intracerebroventricular -MSH
potentiates the hypoactivity resulting from LPS treatment. Both of the
tested intracerebroventricular doses of -MSH suppressed locomotor
activity in the fasted LPS-treated rats. This appeared to be a
behavioral action rather than a result of any impairment of motor
system function per se, because the animals exhibited normal posture
and no neurological signs of motor dysfunction or difficulty (e.g.,
tremor, rotation, freezing, etc.) and the effects were not observed in
the absence of LPS treatment. To our knowledge, the effects of
centrally administered melanocortins on general motor activity in
LPS-treated animals have not previously been studied. Most previous
studies of melanocortin effects on motor-related behaviors have
concerned their stimulatory effects on grooming behavior, which are
generally manifested within a higher dose range than that used in the
present study (1, 3). In the present studies, no evidence of altered
grooming behaviors, including face washing, scratching, paw and tail
licking, or shakes, was noted, probably due to the low
intracerebroventricular doses of -MSH used.
The mechanisms involved in -MSH-induced suppression of locomotor
activity are unknown, but one factor that may have contributed to this
effect is the observed reduction in feeding behavior by -MSH. After
the overnight fast, hunger was presumably the primary motivation for,
and feeding-related movement a major source of, bodily movement during
the light (normally inactive) phase in LPS-treated rats. Consistent
with this possibility, the suppression of locomotion by -MSH was
first exhibited during the light phase (0-8 h after LPS),
concomitant with its potentiation of LPS-induced anorexia, whereas LPS
treatment alone did not significantly inhibit locomotion during this
period. However, the -MSH-induced hypoactivity cannot be wholly
attributed to its suppression of feeding behavior, because
intracerebroventricular SHU-9119 treatment reversed LPS-induced suppression of food intake without affecting LPS-induced suppression of
locomotion. Moreover, the latter finding clearly establishes that the
contribution of endogenous melanocortins to LPS-induced anorexia
represents a behavioral influence rather than a result of any
impairment of normal motor system functions.
The persistence of the suppressive effect of -MSH on locomotion
contrasted with that of its antipyretic effect. The higher -MSH dose
significantly reduced locomotion during the 21- to 24-h post-LPS
period, whereas both the antipyretic effect of -MSH and the
suppressive effect of LPS alone on locomotion had subsided by that
time. These findings further underscore the divergent effects of
melanocortins on different aspects of the acute phase response.
The specific brain MCR subtype(s) involved in mediating the anorexic
effects of melanocortins in LPS-treated rats cannot be determined from
this study, but a potential role of the MC4-R and/or MC3-R is
suggested by several lines of evidence. First, MC3-R and MC4-R are the
predominant MCR mRNA subtypes for which mRNA transcripts are known to
be expressed in rat brain. In contrast, mRNA encoding the other
principal MCR subtype reportedly expressed in the rat brain, MC5-R, is
of very low abundance, as it is not detectable by sensitive RNAse
protection assay or in situ hybridization but only by the
ultrasensitive polymerase chain reaction (32). Second, SHU-9119, which
reversed LPS-induced anorexia after intracerebroventricular injection,
is an antagonist having similar potencies on the rat MC3-R and rat
MC4-R in vitro, but is a full agonist of the MC5-R subtype (10, 11).
The effect of SHU-9119 on LPS-induced anorexia probably reflects MCR
antagonism rather than agonism, because -MSH, which is a
nonselective MCR agonist, potentiated, rather than inhibited,
LPS-induced suppression of feeding behavior. Third, a physiological
role of MC4-R in mediating anorexic central actions of melanocortins in
normal animals is strongly supported by studies involving antagonist
and agonist administration (6, 28), genetic ablation of MC4-R (13), and
overexpression of the native MC4-R and MC3-R antagonist proteins agouti
and agouti-related peptide (21, 36).
In summary, the present results demonstrate that melanocortins modulate
different aspects of the acute phase response in a highly selective and
qualitatively different manner. Centrally administered -MSH
exacerbates LPS-induced anorexia and hypoactivity, and endogenous
melanocortins appear to contribute to LPS-induced anorexia, despite
their ameliorating influence on LPS-induced fever. -MSH and MCR
antagonist treatments were ineffective in the absence of LPS treatment,
suggesting that responsiveness to their effects is cytokine dependent.
These findings indicate that the influence of centrally acting
melanocortins on the coordinated host response to inflammation and
infection extends to behavioral and metabolic activities involved in
the regulation of energy balance.
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ACKNOWLEDGEMENTS |
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We thank Dr. Wei Yuan for preparing SHU-9119.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants MH-44694 (to J. B. Tatro) and DK-17420 (to V. J. Hruby).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: J. B. Tatro, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Box 268, New England Medical Center, 750 Washington St., Boston, MA 02111.
Received 15 October 1998; accepted in final form 8 December 1998.
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REFERENCES |
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Top
Abstract
Introduction
METHODS
Results
Discussion
References
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1.
Bertolini, A.,
R. Poggioli,
and
A. V. Vergoni.
Cross-species comparison of the ACTH-induced behavioral syndrome.
Ann. NY Acad. Sci.
525:
114-129,
1988[Medline].
2.
Catania, A.,
and
J. M. Lipton.
-Melanocyte stimulating hormone in the modulation of host reactions.
Endocr. Rev.
14:
564-576,
1993[Medline].
3.
DeWied, D.,
and
J. Jolles.
Neuropeptides derived from pro-opiocortin: behavioral, physiological and neurochemical effects.
Physiol. Rev.
62:
976-1059,
1982
4.
Dinarello, C. A.
Biological basis for interleukin-1 in disease.
Blood
87:
2095-2147,
1996
5.
Faggioni, R.,
J. Fuller,
A. Moser,
K. R. Feingold,
and
C. Grunfeld.
LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R181-R186,
1997
6.
Fan, W.,
B. A. Boston,
R. A. Kesterson,
V. J. Hruby,
and
R. D. Cone.
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.
Nature
385:
165-168,
1997[Medline].
7.
Fantuzzi, G.,
H. Zheng,
R. Faggioni,
F. Benigni,
P. Ghezzi,
J. D. Sipe,
A. R. Shaw,
and
C. A. Dinarello.
Effect of endotoxin in IL-1 beta-deficient mice.
J. Immunol.
157:
291-296,
1996[Abstract].
8.
Fattori, E.,
M. Cappelletti,
P. Costa,
C. Sellitto,
L. Cantoni,
M. Carelli,
R. Faggioni,
G. Fantuzzi,
P. Ghezzi,
and
V. Poli.
Defective inflammatory response in interleukin 6-deficient mice.
J. Exp. Med.
180:
1243-1250,
1994
9.
Grunfeld, C.,
C. Zhao,
J. Fuller,
A. Pollock,
A. Moser,
J. Friedman,
and
K. R. Feingold.
Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.
J. Clin. Invest.
97:
2152-2157,
1996[Medline].
10.
Hruby, V. J.,
D. Lu,
S. D. Sharma,
A. L. Castrucci,
R. A. Kesterson,
F. A. Al-Obeidi,
M. E. Hadley,
and
R. D. Cone.
Cyclic lactam -melanotropin analogues of Ac-Nle4-cyclo[Asp5,D-Phe7,Lys10]--melanocyte-stimulating hormone(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors.
J. Med. Chem.
38:
3454-3461,
1995[Medline].
11.
Huang, Q.-H.,
M. L. Entwistle,
J. D. Alvaro,
R. S. Duman,
V. J. Hruby,
and
J. B. Tatro.
Antipyretic role of endogenous melanocortins mediated by central melanocortin receptors during endotoxin-induced fever.
J. Neurosci.
17:
3343-3351,
1997
12.
Huang, Q.-H.,
V. J. Hruby,
and
J. B. Tatro.
Systemic -MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release.
Am. J. Physiol.
275 (Regulatory Integrative Comp. Physiol. 44):
R524-R530,
1998
13.
Huszar, D.,
C. A. Lynch,
V. Fairchild-Huntress,
J. H. Dunmore,
Q. Fang,
L. R. Berkemeier,
W. Gu,
R. A. Kesterson,
B. A. Boston,
R. D. Cone,
F. J. Smith,
L. A. Campfield,
P. Burn,
and
F. Lee.
Targeted disruption of the melanocortin-4 receptor results in obesity in mice.
Cell
88:
131-141,
1997[Medline].
14.
Kent, S.,
K. W. Kelley,
and
R. Dantzer.
Effects of lipopolysaccharide on food-motivated behavior in the rat are not blocked by an interleukin-1 receptor antagonist.
Neurosci. Lett.
145:
83-86,
1992[Medline].
15.
Kluger, M. J.
Fever: role of pyrogens and cryogens.
Physiol. Rev.
71:
93-127,
1991[Abstract].
16.
Kozak, W.,
H. Zheng,
C. A. Conn,
D. Soszynski,
L. H. T. Van der Ploeg,
and
M. J. Kluger.
Thermal and behavioral effects of lipopolysaccharide and influenza in interleukin-1-deficient mice.
Am. J. Physiol.
269 (Regulatory Integrative Comp. Physiol. 38):
R969-R977,
1995
17.
Langhans, W.,
D. Savoldelli,
and
S. Weingarten.
Comparison of the feeding responses to bacterial lipopolysaccharide and interleukin-1 beta.
Physiol. Behav.
53:
643-649,
1993[Medline].
18.
Leon, L. R.,
W. Kozak,
J. Peschon,
and
M. J. Kluger.
Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R563-R569,
1997
19.
Ludwig, D. S.,
K. G. Mountjoy,
J. B. Tatro,
J. A. Gillette,
R. C. Frederich,
J. S. Flier,
and
E. Maratos-Flier.
Melanin concentrating hormone: a functional melanocortin antagonist in the hypothalamus.
Am. J. Physiol.
274 (Endocrinol. Metab. 37):
E627-E633,
1998
20.
McCarthy, D. O.,
M. J. Kluger,
and
A. J. Vander.
The role of fever in appetite suppression after endotoxin administration.
Am. J. Clin. Nutr.
40:
310-316,
1984
21.
Ollman, M. M.,
B. D. Wilson,
Y.-K. Yang,
J. A. Kerns,
Y. Chen,
I. Gantz,
and
G. S. Barsh.
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.
Science
278:
135-138,
1997
22.
Plata-Salamán, C. R.
Immunoregulators in the nervous system.
Neurosci. Biobehav. Rev.
15:
185-215,
1991[Medline].
23.
Poggioli, R.,
A. V. Vergoni,
and
A. Bertolini.
ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists.
Peptides
7:
843-848,
1986[Medline].
24.
Rajora, N.,
G. Boccoli,
D. Burns,
S. Sharma,
A. P. Catania,
and
J. M. Lipton.
-MSH modulates local and circulating tumor necrosis factor- in experimental brain inflammation.
J. Neurosci.
17:
2181-2186,
1997
25.
Rivier, C.,
R. Chizzonite,
and
W. Vale.
In the mouse, the activation of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide (endotoxin) is mediated through interleukin-1.
Endocrinology
125:
2800-2805,
1989[Abstract].
26.
Sarraf, P.,
R. C. Frederich,
E. M. Turner,
G. Ma,
N. T. Jaskowiak,
D. J. Rivet,
J. S. Flier,
B. B. Lowell,
D. L. Fraker,
and
H. R. Alexander.
Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.
J. Exp. Med.
185:
171-175,
1997
27.
Satoh, N.,
Y. Ogawa,
G. Katsuura,
Y. Numata,
H. Masuzaki,
Y. Yoshimasa,
and
K. Nakao.
Satiety effect and sympathetic activation of leptin are mediated by hypothalamic melanocortin system.
Neurosci. Lett.
249:
107-110,
1998[Medline].
28.
Seeley, R. J.,
K. A. Yagaloff,
S. L. Fisher,
P. Burn,
T. E. Thiele,
G. van Dijk,
D. G. Baskin,
and
M. W. Schwartz.
Melanocortin receptors in leptin effects.
Nature
390:
349,
1997[Medline].
29.
Shalts, E.,
Y.-J. Feng,
M. Ferin,
and
S. L. Wardlaw.
Alpha-melanocyte-stimulating hormone antagonizes the neuroendocrine effects of corticotropin-releasing factor and interleukin-1-alpha in the primate.
Endocrinology
131:
132-138,
1992[Abstract].
30.
Sonti, C.,
S. E. Ilyin,
and
C. R. Plata-Salamán.
Anorexia induced by cytokine interactions at pathophysiological concentrations.
Am. J. Physiol.
270 (Regulatory Integrative Comp. Physiol. 39):
R1394-R1402,
1996
31.
Swiergiel, A. H.,
G. N. Smagin,
and
A. J. Dunn.
Influenza virus infection of mice induces anorexia: comparison with endotoxin and interleukin-1 and the effects of indomethacin.
Pharmacol. Biochem. Behav.
57:
389-396,
1997[Medline].
32.
Tatro, J. B. Melanocortin receptor expression and
function in the nervous system. In: The Melanocortin
Receptors, edited by R. D. Cone. Totowa: NJ:
Humana, In press.
33.
Thiele, T. E.,
G. Van Dijk,
K. A. Yagaloff,
S. L. Fisher,
M. Schwartz,
P. Burn,
and
R. Seeley.
Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion.
Am. J. Physiol.
274 (Regulatory Integrative Comp. Physiol. 43):
R248-R254,
1998
34.
Uehara, A.,
Y. Ishikawa,
T. Okumura,
K. Okamura,
C. Sekiya,
Y. Takasugi,
and
M. Namiki.
Indomethacin blocks the anorexic action of interleukin-1.
Eur. J. Pharmacol.
170:
253-260,
1989.
35.
Uehara, Y.,
H. Shimizu,
N. Sato,
Y. Tanaka,
Y. Shimomura,
and
M. Mori.
Carboxy-terminal tripeptide of alpha-melanocyte-stimulating hormone antagonizes interleukin-1 induced anorexia.
Eur. J. Pharmacol.
220:
119-122,
1992[Medline].
36.
Yen, T. T.,
A. M. Gill,
L. G. Frigeri,
G. S. Barsh,
and
G. L. Wolff.
Obesity, diabetes, and neoplasia in yellow Avy/
mice: ectopic expression of the agouti gene.
FASEB J.
8:
479-488,
1994[Abstract].
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