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Departments of Neuroscience (B.X., S.P.K.), Physiology (M.G.D., P.S.K.), and Surgery (A.K., L.L.M.) and ICBR (W.G.F.), University of Florida College of Medicine, Gainesville, Florida 32610; and Amgen, Inc. (D.M.), Boulder, Colorado 80301
Address all correspondence and requests for reprints to: Satya P. Kalra, Ph.D., Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida 32610-0244. E-mail: skalra{at}neocortex.health.ufl.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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Exp 1
In this experiment the effects of recombinant rat CNTF (Amgen,
Boulder, CO) administration on hypothalamic prepro-NPY messenger RNA
(mRNA) levels were evaluated. The selection of CNTF dose was based on
previous studies (8, 9, 10, 11, 12). Two groups of freely fed (FF) rats received
either saline alone or CNTF in saline (250 µg/kg) ip at 1000 h
daily for 4 days. Another group of PF rats that received the average of
amount of food consumed by CNTF-treated rats was injected with saline
ip daily at 1000 h. Food intake and body weight were monitored
daily. Twenty-four hours after the fourth injection, rats were killed
by decapitation. The brains were rapidly removed, and the medial basal
hypothalamus (MBH) was dissected, frozen on dry ice, and stored at -80
C for NPY mRNA analysis with a ribonuclease (RNase) protection assay
(30).
Exp 2
In this experiment the effects of intracerebroventricular (icv)
administration of CNTF on hypothalamic NPY gene expression were
examined. Rats were implanted with a permanent cannula in the lateral
cerebroventricle under ketamine/xylazine (30) anesthesia. After a
recovery period of 10 days, rats were randomly divided into four
groups, designated FF, FD, PF, and CNTF. FF, FD, and PF rats were
injected icv daily at 1000 h with phosphate buffer (PBS; 3 µl),
and the CNTF group received CNTF (0.5 µg in 3 µl PBS) for 4 days.
Body weight and food intake were monitored. Rats were killed 24 h
after the fourth icv injection. The MBH was processed for NPY mRNA
analysis as described above.
Two additional groups of FF rats implanted with permanent lateral ventricle cannulas were injected icv with PBS or CNTF (5 µg/3 µl PBS) daily for 4 days as described above. These rats were killed 24 h after the last icv injection, and the MBH was processed for NPY mRNA.
Exp 3
To investigate the effects of CNTF on NPY-induced food intake,
FF rats were preimplanted with permanent lateral ventricle cannulas as
described above. CNTF (0.5 or 5 µg/rat) or PBS (control) was injected
icv daily at 0900 h. On days 1 and 4 of treatment these rats
received NPY (1 nmol/3 µl PBS·rat) icv 1 h after the injection
of CNTF or PBS, and 2-h food intake was measured. This dose of NPY has
been shown to produce a near-maximal increase in food intake in
satiated rats (31).
Exp 4
To analyze the effects of CNTF on leptin mRNA levels in
lipocytes, rats were injected ip with either PBS or CNTF (250 µg/kg)
and killed 5 h later. Epididymal fat was collected and rapidly
frozen at -80 C for subsequent analysis of leptin mRNA. In the second
series of experiments, groups of FF, FD, and PF rats received daily
injections of PBS, and the fourth group received CNTF (250 µg/kg) ip
for 4 days. Rats were killed 24 h after the fourth injection.
Epididymal fat from these rats was processed for leptin mRNA
analysis.
In the third series of experiments, the effects of daily icv injections of CNTF on leptin mRNA were analyzed. As described for Exp 2, groups of rats received daily either PBS (3 µl/rat) or CNTF (5 µg in 3 µl PBS/rat, icv) for 4 days. Epididymal fat samples were collected 24 h after the fourth injection for leptin mRNA analysis.
Exp 5
The effects of daily icv recombinant leptin (rMuleptin, Amgen,
Thousand Oaks, CA) injection on hypothalamic prepro-NPY mRNA
levels were examined. Rats with permanent lateral ventricle cannulas
received daily either PBS (7 µl) or leptin (7 µg/7 µl PBS) for 4
days and were killed 24 h after the last injection. The MBH was
dissected out for analysis of NPY mRNA.
Exp 6
The effects of daily icv injection of leptin (3.5 or 7 µg) or
PBS on NPY-induced food intake were studied. The experimental design
was the same as that described for Exp 3, except that instead of CNTF,
leptin was injected daily. On days 1 and 4, leptin injection was
followed 1 h later by the injection of 1 nmol NPY icv. Two-hour
food intake after the NPY injection was monitored.
RNase protection assay for NPY and leptin
The leptin probe was constructed using the rat leptin plasmid in
pGEM-T vector (Promega), which was ligated with a 318-bp complementary
DNA (cDNA) fragment obtained from reverse transcription-PCR using a
19-mer upper primer (5'-CCC ATT CTG AGT TTG TCC A-3'; 5' position 262)
and an 18-mer lower primer (5'-GCA TTC AGG GCT AAG GTC-3'; 3' position
561) based on rat leptin cDNA (GenBank accession no. D45862) (32).
Total RNA isolated from rat fat tissue with RNA STAT-60 (Tel-Test,
Friendswood, TX) was used for reverse transcription. The plasmid DNA
was linearized by digestion with Spe I, and an antisense probe of 364
bp was produced by in vitro transcription using T7 RNA
polymerase. Total RNA (5 µg) was hybridized overnight at 45 C with
32P-labeled leptin antisense probe and 152-bp ß-actin
antisense riboprobe (cDNA template purchased from Ambion, Austin, TX).
After hybridization, RNase A/T1 digestion was performed for 1 h at
37 C. Protected hybrids were isolated by ethanol precipitation and
separated on a 6% polyacrylamide denaturing sequencing gel. The dried
gel was quantitated by a Molecular Dynamics PhosphorImager (Sunnyvale,
CA). The expected protected leptin fragments and ß-actin fragments
were 318 and 126 bp, respectively. Leptin mRNA levels were standardized
relative to the ß-actin value to minimize gel loading variations.
Complementary DNA to NPY was obtained from Dr. S. L. Sabol (NIH, Bethesda, MD). The standard RNase protection assay protocol, followed for hypothalamic prepro-NPY mRNA was described previously (30). The hybrid signal was analyzed by PhosphorImager, and the NPY mRNA values were normalized to cyclophilin mRNA.
Statistical analysis
Data are presented as the mean ± SE. Leptin
and prepro-NPY mRNA in various experiments were measured in several
RNase protection assays at different times. Although the leptin and NPY
mRNA values were calculated relative to ß-actin and cyclophilin in
each sample, due to variations in sensitivities of the ß-actin and
cyclophilin probes in different assays, the mRNA values for controls
varied between experiments. To make comparisons between experiments,
the mRNA values for controls were assigned an arbitrary value of 1.0,
and the levels in experimental groups were calculated relative to this.
Data were statistically analyzed by one-way ANOVA followed by Tukey’s
multiple comparison test post-hoc. Daily body weight changes
are presented as a percentage of the initial body weight. Body weight
changes and food intake within a group were analyzed by repeated
measures ANOVA and Dunnett’s multiple test to compare with initial
values. Comparisons between two treatment groups at any single time
point or dose level were made by the unpaired t test for two
groups and by one-way ANOVA followed by Tukey’s multiple comparison
test post-hoc for more than two groups. The level of
significance was set at P < 0.05.
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Results |
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)) significantly reduced 24-h food
intake in a time-related fashion, with the lowest intake observed after
the fourth CNTF injection. Whereas FF rats injected with saline
maintained their body weight, the anorexia in CNTF-treated rats
resulted in a significant loss in body weight beginning on day 2
(P < 0.05) and reaching the lowest level on day 4
(Fig. 1B). PF rats that were fed amounts equivalent to CNTF rats showed
a pattern of body weight loss similar to that of the CNTF-treated rats.
The effects of these treatments on hypothalamic NPY gene expression are
shown in Fig. 1C. In association with reduced intake and loss in body
weight, the steady state prepro-NPY mRNA levels in the hypothalami of
PF rats increased significantly compared with that in FF control rats
(P < 0.05). However, in CNTF-treated rats, despite a
similar loss in body weight, there was no increase in NPY gene
expression; prepro-NPY mRNA levels in the hypothalami of CNTF-treated
rats were similar to those in saline-injected FF rats.
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and 3)) produced a
significant decrease in food intake and loss of body weight compared
with those in FF rats (P < 0.05). A decrease in food
intake to about 50% of the control range was seen between days 2 and 4
in CNTF-treated rats (Fig. 2A); the loss in body weight in these rats
was comparable to that observed in PF rats, but was significantly
less than that seen in FD rats (P < 0.05; Fig. 2B).
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, hypothalamic NPY gene expression was augmented in
PF rats compared with that in FF control rats (P <
0.05) and was even further increased in FD rats (P
< 0.05 vs. PF rats). Despite the anorexia and loss in body
weight equivalent to those observed in PF rats, NPY gene expression
failed to increase in CNTF-treated rats. In fact, prepro-NPY mRNA
levels in these rats were similar to those in FF rats (Fig. 2C).
Further, as shown in Fig. 3, a 10-fold
higher dose of icv CNTF (5 µg/rat) also reduced food intake, and the
loss in body weight was slightly greater (15% of initial body weight)
than that in response to 0.5 µg CNTF (12% of initial body weight;
Fig. 2). However, in contrast to the lack of effect of 0.5 µg CNTF
treatment (Fig. 2C) on NPY mRNA levels, the higher dose of CNTF
significantly suppressed the steady state levels of prepro-NPY mRNA
below those in FF control rats (P < 0.05; Fig. 3C).
Effects of icv CNTF on NPY-induced feeding (Fig. 4)
To investigate the effects of daily 0.5- and 5-µg CNTF treatment
on NPY-induced feeding, we analyzed 2-h food intake in response to NPY
(1 nmol) on days 1 and 4 of treatment. As expected on both days 1 and
4, NPY evoked robust feeding responses in control rats injected with
PBS daily. Rats injected with CNTF alone (0.5 or 5 µg) ate a little,
but this response was not different from that in the controls or that
seen normally in untreated rats (31). In rats pretreated with CNTF,
decreases in NPY-induced food intake were observed on day 1; however,
the decrease was statistically significant only in the group receiving
5 µg CNTF (P < 0.05). On day 4, NPY-induced food
intake was suppressed in rats receiving either dose of CNTF, and the
magnitude of suppression was related to the dose of CNTF
(P < 0.05).
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Effects of ip CNTF. As shown in Fig. 5A, one injection of CNTF failed to alter
leptin mRNA levels in the lipocytes when analyzed 5 h later.
However, daily injections of CNTF produced a profound suppression of
leptin mRNA in lipocytes in association with a loss in body weight. In
accord with the results of Exp 1 presented in Fig. 1, in this
experiment FF rats increased body weight by 15% during the 4-day
treatment with PBS compared with their initial body weight, whereas
CNTF-treated rats lost 5% of their body weight, equivalent to that
seen in PF rats, but significantly less than that in FD rats (22%;
data not shown). As shown in Fig. 5B, this CNTF treatment decreased
lipocyte leptin mRNA (P < 0.05 vs. FF
control rats); the reduction in leptin gene expression was similar to
those in FD and PF rats.
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, daily icv injections of 5 µg CNTF for 4 days reduced body
weight by 15% (P < 0.05; data not shown). This loss
in body weight was accompanied by a significant decrease in leptin mRNA
in lipocytes of CNTF-treated compared with control PBS-injected rats
(Fig. 6).
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, icv NPY (1 nmol)
induced a robust feeding response on both days 1 and 4 in control rats
injected daily with PBS. Injection of leptin (3.5 or 7 µg) 1 h
before NPY on day 1 reduced food intake, but the response was not
statistically significant. However, on day 4 of leptin treatment (3.5
or 7 µg), NPY-induced feeding was significantly reduced; feeding was
reduced by 88% in 3.5 µg leptin-treated rats and by 90% in rats
treated with 7 µg leptin (P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NPY is a potent endogenous orexigenic signal (15, 16). Our findings show that CNTF may act on hypothalamic NPYergic signaling in three ways to produce anorexia. First, it is likely that the supply of NPY for release at the appetite-stimulating targets located in the PVN and surrounding sites (15, 16, 19, 20) may be drastically curtailed. This is evidenced by our findings that CNTF inhibited the basal steady state levels of prepro-NPY mRNA in the ARC by high doses of CNTF and suppressed the augmentation in NPY gene expression normally produced by restricted feeding or fasting. In fact, the degree of suppression of NPY gene expression was positively correlated with the dose of CNTF and the reduction in food intake. Second, CNTF injected ip or icv in small doses produced anorexia, with no change in hypothalamic prepro-NPY mRNA compared with that in freely fed controls. Seemingly, the supply of NPY for release may not be disrupted under these conditions. Although the current studies do not provide any supportive evidence, it remains possible that the amount of NPY release responsible for normal food intake may be attenuated in CNTF-treated rats, thereby leading to decreased food intake. Indeed, immunoneutralization of endogenously released NPY has been shown to suppress food intake and induce a loss in body weight in a fashion similar to that seen in CNTF-treated rats (23). Third, CNTF suppressed the feeding induced by NPY. Suppression of intake in response to NPY was evident on day 1 of CNTF treatment, and the magnitude of suppression was highest on day 4. These findings lead us to suspect that an additional site of CNTF action in counteracting NPY-induced appetite most likely resides in the PVN and surrounding areas, where NPY microinjection readily stimulated feeding (36). Overall, these revelations strongly imply that CNTF-induced body weight loss is the consequence of anorexia caused by a reduction in the NPY supply for release, possibly release itself, and suppression of NPY action at hypothalamic target sites engaged in enhancing appetite.
These conclusions are supported by another line of evidence. It is
known that energy depletion produced by either restricted availability
or complete absence of food up-regulates NPY synthesis and release
(19, 20, 21), which, in turn, is apparently responsible for enhancing
appetite to replenish the loss in energy (19, 23). These
energy-depleted rats feed avidly when allowed access to food and
quickly regain the loss in body weight. In our study, food and water
were available ad libitum to CNTF-treated rats, and despite
the disruption in energy homeostasis similar to that in PF and FD rats,
as indicated by weight loss, these rats apparently made little attempt
to replenish the energy loss. Also, we observed that daily icv CNTF
administration to fasted rats prevented the fasting-induced
up-regulation of NPY expression in the hypothalamus (37). Taken
together, these findings clearly show that CNTF is a powerful appetite
suppressant and curtailment of NPYergic signaling in the hypothalamus
may in part underlie the anorexia. The precise mechanism by which CNTF
reduces both NPY gene expression and action, presumably at two
different sites in the hypothalamus, remains to be ascertained.
Although the topography of the neuronal network producing CNTF in the
hypothalamus is currently unknown, both CNTF receptor-
immunoreactivity and CNTF receptor- mRNA are expressed in various
hypothalamic sites, including the PVN (38, 39). Thus, the potential to
influence the NPYergic system by CNTF exists in the adult rat
hypothalamus.
Concurrent with the loss in body weight due to anorexia, we observed that the steady state leptin mRNA levels were reduced in the lipocytes of CNTF-treated rats. These findings complement several reports showing that leptin gene expression in fat cells is directly related to body mass index (reviewed in Refs. 28 and 40). However, we suspect that the act of eating itself may serve as a trigger to up-regulate leptin gene expression, and the anorexia in CNTF-treated rats may be responsible for diminished leptin gene expression. This inference is in harmony with a number of observations that the daily increases in leptin gene expression in lipocytes and the circulating levels of leptin closely follow the normal feeding pattern during the night (28, 39).
Our consistent findings of a reduction in leptin gene expression in lipocytes by CNTF administered either systemically or centrally differ from those reported for several other peripherally administered cytokines, such as tumor necrosis factor, interleukin-1, and leukemia inhibitor factors as well as the endotoxin, lipopolysaccharide (33, 34). These cytokines were shown to augment leptin secretion and lipocyte leptin gene expression, both acutely and on a long term basis in fasted mice and free-fed hamsters. Based on these results, it was suggested that the cytokine-induced increase in leptin may be responsible for the anorexia seen in these rodents (34, 35). In contrast, our results show that ip CNTF failed to change leptin mRNA acutely in satiated rats, an observation similar to that reported in fasted mice (33). In addition, severe anorexia in conjunction with reduced leptin mRNA was observed in rats receiving CNTF either systemically or centrally. Consequently, our findings demonstrate that anorexia produced by CNTF involves a direct central action mediated through diminution in NPYergic signaling and not indirectly via up-regulation of leptin.
Additionally, a comparison of our results of CNTF and leptin studies clearly show that these two members of the cytokine family engage a similar central modality, i.e. suppression of NPY synthesis and action in the hypothalamus, to cause anorexia. Evidently, these cytokines suppress the basal, as shown in this study, and fasting-induced NPY gene expression (37), and in this respect, although additional studies are needed, CNTF appears slightly more effective than leptin on a molar basis. However, in each of these two cases anorexia at the doses tested was quite severe, and injection of NPY only marginally stimulated feeding in these rats. Therefore, we are tempted to propose that CNTF and leptin may involve similar intracellular JAK-STAT signal transduction modalities in target cells in the hypothalamus to produce anorexia leading to body weight loss (41, 42, 43).
In summary, the results of these studies show that CNTF is a potent anorectic cytokine. One of the central CNTF actions in producing anorexia and body weight loss involves suppression of NPYergic signaling in the hypothalamus in a manner similar to that effected by leptin. Identification of the NPY neuronal system as one of the target neural pathways for CNTF action is important for further understanding the cellular and molecular events underlying the anorexia accompanying infection and brain injury.
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Acknowledgments |
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Footnotes |
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Received July 9, 1997.
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expression in the rat nervous system.
J Neurosci 16:621–630 messenger RNA in neonatal and
adult rat brain: an in situ hybridization study.
Neuroscience 77:233–246[CrossRef][Medline]
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