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Endocrinology |
Department of Pediatric Endocrinology [D. L. M.], Vollum Institute [R. D. C.], Oregon Health Sciences University, Portland, Oregon 97201, and Neurocrine Biosciences, Inc. [N. L.], San Diego, California
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cachexia is commonly observed in patients with cancer, particularly in children and elderly individuals (19) . The resulting malnutrition and loss of lean body mass reduces the quality of life for the affected individual and compromises recovery by decreasing tolerance to therapy and increasing postsurgical complications (2 , 7) . Attempts at drug therapy for cachexia with a variety of agents have met with limited success (20, 21, 22, 23) . The most widely used agent, megestrol acetate, has shown some promise in reversing weight loss, but this is primarily attributable to increases in fat mass and water retention rather than preservation of lean body mass (24) . Various murine models of cancer cachexia exist that recapitulate the anorexia, rapid weight loss, and catabolism of body protein stores found in human cancer patients. Subcutaneous injections of Lewis lung adenocarcinoma or various types of methylcholanthrene-induced sarcomas reliably produce cachexigenic tumors in mice and, therefore, provide useful models for genetic and pharmacological analysis of this disorder and its potential treatment (25, 26, 27, 28) .
POMC is a propeptide precursor that is produced in neurons found in the
hypothalamic arcuate nucleus (29)
. POMC neurons are
thought to provide an important tonic inhibition of food intake and
energy storage, primarily via production and release of 
-MSH from
the POMC precursor. -MSH binds to central melanocortin receptors
(including MC4-R). Central administration of MC4-R agonists can inhibit
energy intake, increase energy expenditure (30
, 31)
, and
reduce body weight (32
, 33)
. In contrast, disruption of
melanocortin signaling with antagonist administration or deletion of
the MC4-R (MC4-RKO) leads to an increase in feeding and eventually to
obesity (30
, 34) . POMC neurons in the arcuate nucleus
express the leptin receptor and MC4-RKO mice are leptin resistant,
leading several investigators to propose that melanocortin neurons
mediate the anorexic and metabolic effects of elevated leptin
(35
, 36)
. Remarkably, leptin is a member of the IL-6
superfamily of proteins and has many biochemical features of a cytokine
molecule (37
, 38) . However, initial studies of
cytokine-induced anorexia in mice with disrupted melanocortin signaling
(viable obese yellow, Avy/a) demonstrated
enhanced anorexia in this model, perhaps because of increased release
of endogenous corticotropin-releasing factor (39
, 40)
. In
a more recent study, Huang et al. demonstrated a reversal of
LPS-induced anorexia in rats treated with a central melanocortin
antagonist (41)
. Thus, it remains plausible that central
melanocortin receptors may integrate a number of physiological signals
that produce the combination of decreased energy intake and increased
energy utilization that characterizes illness-induced cachexia. To test
the potential role of central melanocortin signaling in the pathology
of cachexia, we examined the effects of central melanocortin blockade
on activity, feeding, and weight homeostasis in several models of
murine cachexia.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cannula Placement.
C57Bl/6J mice were anesthetized with halothane and placed in a
stereotaxic apparatus (Cartesian Research, Inc.). A sterile guide
cannula with obdurator stylet was stereotaxically implanted for i.c.v.
injection with the coordinates of 0.5 mm posterior to the bregma,
1–1.6 mm lateral to the midline, and 2 mm below the bregma. The
cannula was then fixed in place using dental cement. The animals were
housed separately after surgery at least 1 week for recovery before
experiments. The positions of the cannulae were verified at the end of
experiments by histological analysis; in animals in which CSF return
was not obvious, the position of the cannulae were tested by dye
administration before the animals were killed.
AGRP and LPS Administration.
Each animal was handled daily for a minimum of 5 consecutive days
before the initiation of the experiment, simulating the restraint used
during the injection of the compounds. ACSF or AGRP diluted in ACSF was
infused in a total volume of 2 µl over 30 s in lateral
ventricle-cannulated mice. In the LPS experiments, LPS
(Escherichia coli 055:B5; Sigma Chemical Co.) was dissolved
in normal saline and administered i.p. MC4-RKO mice and littermate
controls had basal feeding monitored for 2 days and then during each
12-h period after an i.p. saline injection (1700 h) before injection of
100 µg/kg LPS. In C57Bl/6 WT animals, AGRP (84–132 amino acid
fragment; Neurocrine Biosciences, Inc., San Diego, CA) was
administered at 1500 h, and 50 µg/kg LPS was administered at
1700 h. A second dose of 100 µg/kg was given 60 h after the
first dose in the second experiment. No food was available between AGRP
administration and LPS administration, and 24-h feeding was measured
starting at 1700 h. In the tumor models, AGRP or ACSF was
administered at 1400 h with each administration.
Tumor Models.
LLC cells and EHS sarcoma tumors were maintained either as a primary
culture in DMEM with 10% fetal bovine serum or in vivo,
respectively, as recommended by the supplier (American Type Culture
Collection, Manassas, VA). LLC tumor cells were harvested during
exponential growth of the culture, washed in HBSS, and 1 x 106 cells were injected s.c. into the
upper flank of the mice. EHS sarcoma tissue was dissected from a donor
animal, and an approximately 3-mm cube of tissue was implanted s.c.
above the rear flank. Sham-operated animals received an implant of a
similar amount of donor muscle tissue. In all cases, the time of
appearance of a tumor mass was noted in the log, and all animals were
found to have a palpable tumor within 4 (LLC) or 8 (EHS) days of the
start of the experiment. At the time the animal was killed, tumors were
dissected away from surrounding tissue and weighed. Gross examination
of all organs did not reveal the presence of any observable metastasis.
Trunk blood was collected at the time the animal was killed for
measurement of serum leptin with a rat leptin RIA kit (Linco Research,
Inc., Manassas, VA).
Motor Activity and Feeding Activity.
Animals were housed individually in metabolic cages equipped with a
running wheel (Mini-Mitter Co., Sunriver, OR). The metabolic cages
usage allowed telemetric monitoring of circadian rhythms as assessed
via multiple physiological parameters. The wheel revolutions were
quantified by recording the magnetic switch closures of a magnet placed
on the revolving wheel. For feeding recordings, feeding counts and
duration were recorded when the animals interrupted an infrared
beam above the feeding chambers.
Statistical Methods.
Differences between feeding, activity, and water consumption curves in
all experiments were analyzed by two-way, repeated measures ANOVA, with
time and treatment as the measured variables. Final tumor and body
weights were analyzed by Student’s t test when two groups
were included, or one-way ANOVA with post hoc analysis when three
groups were included. Data sets were analyzed for statistical
significance using either the PRISM software package (GraphPad) for
ANOVA with repeated measures or EXCEL (Microsoft) using Student’s
t test.
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RESULTS |
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, even in the 24- to 36-h period after LPS treatment.
Feeding was measured every 6 h for 24 h and then every
12 h for 48 h more. The difference between feeding curves was
significant when expressed both as weight-normalized intake
(n = 6, P < 0.001,
Fig. 1B
) and as a percentage of basal feeding
(n = 6, P < 0.001
versus postsaline and sham i.c.v. injection, data not
shown). Thereafter, the ACSF-treated group demonstrated a recovery of
normal feeding as expected (24-h feeding from 36 to 58 h
post-LPS; 91 ± 3 g/kg0.75
AGRP versus 92 ± 8
g/Kg0.75 ACSF, P = 0.98). AGRP also prevented weight loss in this model of illness
(n = 6, P < 0.0001, Fig. 1C
). In a second experiment, a second dose of
LPS (100 µg/kg) was given after recovery from the first dose 3 days
after the first LPS injection (Fig. 1D)
. In this experiment,
the ACSF-treated animals recovered to 95% of basal feeding on the 3rd
day after the first LPS injection, after showing a significant drop in
food intake relative to the AGRP group (n = 7
AGRP, n = 6 ACSF, P < 0.0001). Interestingly, the AGRP-treated animals continued to
show a relative hyperphagia and consumed 118 ± 6% of
basal food intake on that day (n = 7,
P < 0.02). The second LPS injection did not
result in a significant decrease in feeding in either group,
demonstrating LPS tolerance in these animals (42)
.
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. This decrease in intake was not seen in MC4-RKO animals
(n = 5, P < 0.01
versus WT) when measured either as total food intake or as a
percentage of basal intake after saline injection (Fig. 2B)
.
Water intake as a percentage of the basal value was also greater in
MC4-RKO mice, but the difference was not significant (MC4-RKO 70 ±12%
versus WT 46 ±14%, P > 0.05).
However, total lick counts were significantly different after LPS
(MC4-RKO 1.8 ± 0.4 cpm versus WT
0.4 ± 0.09 cpm, P < 0.05).
Wheel running activity was similar between groups after saline
injection but greatly decreased in the WT animals after LPS injection
(Fig. 2C)
. Twenty-four-h total number of turns per min was
similar after saline injection (MC4-RKO 2.5 ± 0.6
turns/min versus WT 2.8 ± 0.8 turns/min,
P = 0.8), whereas after LPS injection, the WT
animals showed a decrease in total 24-h turns, whereas MC4-RKO animals
maintained normal activity (MC4-RKO 2.4 ± 0.9 turns/min
versus WT 0.1 ± 0.05 turns/min,
P < 0.05). WT animals failed to gain weight
during the 60-h experimental period, whereas MC4-RKO mice continued to
gain weight (Fig. 2D, P
< 0.05).
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, AGRP injected 96 ± 5% on day 14).
However, the difference between treatment groups was not significant on
that day (n = 5, P = 0.2). A second injection on day 14 postimplant sustained this
normalization of food intake, whereas the ACSF-treated animals
continued to have gradually decreasing intake. This effect lasted for 3
days, with a return to the relatively anorexic state by day 18
postimplant. A third injection of AGRP on this day again raised the
food intake of AGRP-treated animals, with both groups killed on day 19
because of the growth of the tumor. Overall ANOVA for feeding in this
study was significant (n = 5,
P < 0.0003), with post hoc testing being
significant on days 16, 17, and 19 after tumor implant. AGRP treatment
had no effect on final tumor mass (AGRP 5.1 ± 1.3 g versus ACSF 6.0 ± 0.8 g,
P = 0.6) but did prevent the weight loss
observed in the ACSF-treated animals (AGRP +2.1 ± 0.8 g versus ACSF -0.21 ± 0.03 g,
P < 0.05). In a second experiment we tested
the ability of AGRP to prevent the onset of cachexia and to maintain
normal feeding and growth. Animals were examined daily for the presence
of a palpable tumor, with all animals having tumors by day 14
postimplantation and none before day 12. Animals were then injected
with AGRP (2.5 nmol in 2 µl ACSF) or ACSF every 48 h until they
were killed. A sham-tumor-implanted group was included for comparison
and was also given AGRP. AGRP administration prevented the
tumor-induced decline in food intake in the AGRP-treated animals and
resulted in a relative hyperphagia in the sham tumor animals (Fig. 3B, P
< 0.0001). Two animals were
removed from the ACSF group 24 h before the end of the experiment
because of moribund appearance. These animals had eaten <20% of basal
amount during the 24 h before they were killed. AGRP treatment did
not affect final tumor mass (Fig. 3D, P
= 0.5) but did prevent the tumor-induced weight loss (Fig. 3C, P
< 0.0001). Postmortem
dissection did not reveal the presence of any discernible s.c.,
epididymal, or visceral fat pads in any experimental group.
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. The overall feeding curves were noticeably different from
that day onward, with the WT animals consuming 56% of MC4-RKO levels
by the final day of the experiment (Fig. 4A
;
n = 5; P < 0.0001). The change in water lick counts paralleled the change in food
consumption (Fig. 4B
; P < 0.0001). WT animals showed a prompt decline in wheel running activity
to 30 ± 10% of basal activity by day 7
postimplantation, whereas MC4-RKO mice showed a slower decline (day 7,
70 ± 14%, P < 0.05).
However, the MC4-KO animals eventually decreased their running activity
as well (66 ±18% of basal on the final day), and the overall activity
curves were not different between groups (n = 5, P = 0.09). MC4-RKO animals gained carcass
weight, whereas control animals lost weight (Fig. 4C
;
n = 5; P < 0.05).
The final tumor mass was not different between groups (Fig. 4D
; P = 0.9). Serum leptin levels
also were not different between groups (WT 2.3 ± 1.4
ng/ml versus KO 2.2 ± 1.1 ng/ml,
P = 0.98). A repeat trial of this experiment
revealed similar results with significant differences observed in
carcass weight change (WT -0.3 ± 0.5 g
versus KO 1.4 ± 0.4 g,
P < 0.05) but not in final tumor mass (WT
1.7 ± 0.3 g versus KO 1.4 ± 0.4 g, P = 0.61). Preliminary
carcass analysis indicated that the majority of the difference between
groups was attributable to a larger amount of lean body tissue in the
MC4-RKO
animals.4
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DISCUSSION |
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One model that has been particularly useful in studying cachexia has
been administration of a purified product found in the cell wall of
Gram-negative bacteria, which is known generically as LPS. Early
experiments focused on the ability of LPS injections to reliably
produce anorexia in experimental animals (13
, 14)
. It is
now known that LPS potently stimulates the release of numerous
cytokines from immune cells in the periphery and glia within the CNS
and that these cytokines are primarily responsible for the observed
response (15, 16, 17, 18)
. Previous studies of the impact of
central melanocortins in transducing signals from cytokines have had
mixed results. In an early study using the AVY
mouse, an enhanced anorexigenic response to peripheral IL1-ß was
observed (40)
. Of course, the MC4-R blockade by
agouti in this model is reversible. In contrast, a recent study
has demonstrated that MC4-RKO mice resist the inhibition of locomotion
produced with central IL1-ß administration (50)
. Huang
et al. investigated the impact of central administration of
-MSH or the melanocortin receptor subtype3/subtype4 antagonist
SHU-9119 on LPS-induced anorexia and fever in rats (41)
.
In this study, the investigators found a significant potentiation of
the suppressive effects of LPS on food intake with administration of
-MSH and a reversal of LPS-induced anorexia with SHU-9119
administration. These same treatments reduced and increased LPS-induced
fever, respectively. Our data are in agreement with these latter
findings and demonstrate that both genetic and pharmacological blockade
of central MC4-R signaling can prevent the hypophagia, hypodipsia, and
decreased locomotor activity seen after induction of a complex and
pleiotropic cytokine response. Additionally, we have also demonstrated
that in young, rapidly growing mice, the weight loss that accompanies
LPS-induced illness can be reversed, allowing the animals to continue
to follow a normal growth curve.
Our data demonstrate a preservation of normal motor activity in MC4-KO animals, which contrasts with the inability of SHU-9119 to restore normal motor activity in LPS-treated rats (41) . Furthermore, we observed very little illness behavior in our AGRP-treated animals after LPS injection. These differences are likely to result from the fact that in our experiments the animals had a blockade of MC4 receptor signaling (with AGRP or in the receptor knock-out mouse) before the injection of LPS and because of the timing of our LPS injections immediately before the onset of the active dark phase. The effect of LPS on motor activity can be detected quite early in the course of the illness, and the systems involved in this suppression may be activated before the onset of melanocortin blockade when LPS is injected before administration of melanocortin antagonists. Additionally, we have observed that AGRP administration produces a prolonged effect (>36 h in the sarcoma-bearing animals), and it is possible that SHU-9119 does not have a sufficient duration of action (relative to LPS) to reverse the inhibition of nocturnal locomotion when both compounds are injected in the morning.
The role of melanocortin receptors in transducing the prolonged metabolic derangement observed in experimental cancer has not been previously reported. Many different tumor types have been studied, and it is a common finding that tumor-bearing animals die from cachexia and exhaustion of metabolic fuels rather than from metastasis or infection (28 , 45 , 51 , 52) . Our observations demonstrate that hypophagia and carcass weight loss induced by sarcoma growth can be both reversed and prevented by administration of the endogenous MC3/MC4 antagonist, AGRP. In this case, the duration of the experiment in the AGRP-treated animals was limited only by ethical concerns because of the size of the tumor rather than by anorexia or lack of physical activity and grooming. When the animals had already become hypophagic because of the growth of the tumor, there was a delay in the response to AGRP injection, with significant induction of feeding seen after the second and third but not the first injection. The presence of this priming effect may be attributable to lasting activation of neurons downstream from MC4 receptors or may simply be attributable to the need for an accumulation of antagonist to overcome a high melanocortin tone. Prevention of tumor-induced hypophagia with early and repeated AGRP injections resulted in a maintenance of normal food intake, and this enhancement of feeding was much greater than the relative hyperphagia observed in the sham-tumor-implanted animals. The inability to completely mimic the feeding observed in the sham-tumor group is likely to reflect, in part, the energy drain imposed by the rapid growth of a metabolically active tissue. However, our observation that the rate of tumor growth was identical between AGRP and vehicle-treated groups argues strongly that tumor growth produces a global metabolic derangement that is primarily mediated by central melanocortin receptor activation. If the tumor simply represented a metabolic sink, increased nutrient intake would be expected to result in increased tumor growth at the expense of nontumor body mass.
Several lines of evidence exist suggesting that the anorexic and metabolic effects of leptin are transduced by hypothalamic melanocortin receptors (53, 54, 55, 56) . Furthermore, LPS injection is known to increase the level of leptin in the circulation, leading to the suggestion that enhanced leptin feedback may be responsible for illness-induced cachexia (57) . Our data argue that the suppression of feeding in our cachexia models is not attributable to enhanced leptin feedback. An increase in plasma leptin was not observed in tumor-bearing animals, and an increase in feeding was observed before any noticeable increase in body weight and without the presence of any grossly detectable increase in body fat. This idea is consistent with previous observations that leptin-deficient ob/ob mice are hypersensitive to the anorexic effects of LPS injections and to the anorexia and weight loss induced by tumor growth (58, 59, 60) . Thus, we propose that the observed effects of melanocortin blockade in our experiments are attributable to a leptin-independent activation of hypothalamic POMC neurons with a resultant increase in activity at the hypothalamic MC4-R.
In summary, hypothalamic MC4-R activation appears to integrate peripheral signals that lead to anorexia, hypodipsia, and decreased locomotion during illness. Blockade of this signal results in normalization of food intake, activity, and growth without increasing the morbidity or mortality observed. This system is operative in both acute (LPS-induced) and chronic (cancer-induced) illness, which reinforces the idea that the hypothalamic melanocortin system provides the primary inhibitory tone on food intake. Our data suggest that this system may play an integrative role in mediating the cachexia observed in human diseases such as cancer, heart failure, Alzheimer’s disease, and AIDS, thereby providing a common target for therapeutic intervention.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by research grants from Neurocrine
Biosciences, Inc., and NIH Grants DK55819, DK51730, and HD07497. 
2 To whom requests for reprints should be
addressed, at Vollum Institute, Mailcode L474, Oregon Health Sciences
University, 3181 SW Sam Jackson Park Road, Portland, OR 97201. Phone:
(503) 494-4667; Fax: (503) 494-4534; E-mail: cone{at}ohsu.edu
3 The abbreviations used are: CNS, central nervous
system; LPS, lipopolysaccharide; POMC, proopiomelanocortin; IL,
interleukin; -MSH, -melanocyte-stimulating hormone; MC4-R, type 4
melanocortin receptor; KO, knock-out; WT, wild-type; i.c.v.,
intracerebroventricular; CSF, cerebrospinal fluid; ACSF, artificial
cerebrospinal fluid; AGRP, agouti-related peptide; LLC, Lewis lung
carcinoma; EHS, Englebreth-Holm-Swarm (sarcoma); NPY, neuropeptide Y.
4 M-A. Pellymounter, personal communication.
Received 8/24/00. Accepted 12/ 8/00.
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REFERENCES |
|---|
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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antibodies attenuate development of cachexia in tumor models.. FASEB J., 3: 1956-1962, 1989.[Abstract]
induces cachexia with redistribution of body proteins. Am. J. Physiol., 256: R659-R665, 1989.
antibody treatment, growth of Lewis lung tumors in mice and tumor-associated cachexia.. Eur. J. Cancer, 27: 182-187, 1991.
-Melanocyte-stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain.. Proc. Natl. Acad. Sci. USA, 75: 6300-6304, 1978.This article has been cited by other articles:
|
|
 |
|
  M. J. Tisdale Mechanisms of Cancer Cachexia Physiol Rev, April 1, 2009; 89(2): 381 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Laviano, A. Inui, D. L. Marks, M. M. Meguid, C. Pichard, F. Rossi Fanelli, and M. Seelaender Neural control of the anorexia-cachexia syndrome Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1000 - E1008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Sartin, D. L. Marks, C. D. McMahon, J. A. Daniel, P. Levasseur, C. G. Wagner, B. K. Whitlock, and B. P. Steele Central role of the melanocortin-4 receptors in appetite regulation after endotoxin J Anim Sci, October 1, 2008; 86(10): 2557 - 2567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. D Madison, J. M Scarlett, P. Levasseur, X. Zhu, K. Newcomb, A. Batra, D. Bowe, and D. L Marks Prostacyclin signaling regulates circulating ghrelin during acute inflammation J. Endocrinol., February 1, 2008; 196(2): 263 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. DeBoer, X. Zhu, P. R. Levasseur, A. Inui, Z. Hu, G. Han, W. E. Mitch, J. E. Taylor, H. A. Halem, J. Z. Dong, et al. Ghrelin Treatment of Chronic Kidney Disease: Improvements in Lean Body Mass and Cytokine Profile Endocrinology, February 1, 2008; 149(2): 827 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Ropelle, J. R. Pauli, K. G. Zecchin, M. Ueno, C. T. de Souza, J. Morari, M. C. Faria, L. A. Velloso, M. J. A. Saad, and J. B. C. Carvalheira A Central Role for Neuronal Adenosine 5'-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia Endocrinology, November 1, 2007; 148(11): 5220 - 5229. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. Cheung, H.-J. Kuo, S. Markison, C. Chen, A. C. Foster, D. L. Marks, and R. H. Mak Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2517 - 2524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. DeBoer, X. X. Zhu, P. Levasseur, M. M. Meguid, S. Suzuki, A. Inui, J. E. Taylor, H. A. Halem, J. Z. Dong, R. Datta, et al. Ghrelin Treatment Causes Increased Food Intake and Retention of Lean Body Mass in a Rat Model of Cancer Cachexia Endocrinology, June 1, 2007; 148(6): 3004 - 3012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hashimoto, Y. Azuma, M. Kawasaki, H. Fujihara, E. Onuma, H. Yamada-Okabe, Y. Takuwa, E. Ogata, and Y. Ueta Parathyroid Hormone-Related Protein Induces Cachectic Syndromes without Directly Modulating the Expression of Hypothalamic Feeding-Regulating Peptides Clin. Cancer Res., January 1, 2007; 13(1): 292 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Cone Studies on the Physiological Functions of the Melanocortin System Endocr. Rev., December 1, 2006; 27(7): 736 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L.J Ellacott and R. D Cone The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models Phil Trans R Soc B, July 29, 2006; 361(1471): 1265 - 1274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Perboni and A. Inui Anorexia in cancer: role of feeding-regulatory peptides Phil Trans R Soc B, July 29, 2006; 361(1471): 1281 - 1289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Nicholson, G. Kohler, F. Schaerer, C. Senn, P. Weyermann, and K. G. Hofbauer Peripheral Administration of a Melanocortin 4-Receptor Inverse Agonist Prevents Loss of Lean Body Mass in Tumor-Bearing Mice J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 771 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wilcock Anorexia: a taste of things to come? Palliative Medicine, January 1, 2006; 20(1): 43 - 45. [PDF]
|
|
|
|
 |
|
 A. Wi""cek How does leptin contribute to uraemic cachexia? Nephrol. Dial. Transplant., December 1, 2005; 20(12): 2620 - 2622. [Full Text] [PDF]
|
|
|
|
|
|
C. W, Y. PX, L. BM, C. RD, M. DL, M. RH, I. H, O. MH, W. K, B.-J. K, et al. Anorexia and Cachexia in Renal Failure--Is Leptin the Culprit?: Role of Leptin and Melanocortin Signaling in Uremia-Associated Cachexia. J Clin Invest 115: 1659-1665, 2005 J. Am. Soc. Nephrol., August 1, 2005; 16(8): 2245 - 2250. [Full Text] [PDF]
|
|
|
|
|
|
S. Markison, A. C. Foster, C. Chen, G. B. Brookhart, A. Hesse, S. R. J. Hoare, B. A. Fleck, B. T. Brown, and D. L. Marks The Regulation of Feeding and Metabolic Rate and the Prevention of Murine Cancer Cachexia with a Small-Molecule Melanocortin-4 Receptor Antagonist Endocrinology, June 1, 2005; 146(6): 2766 - 2773. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Deshmukh, B. G. Phillips, T. O'Dorisio, M. J. Flanigan, and V. S. Lim Hormonal responses to fasting and refeeding in chronic renal failure patients Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E47 - E55. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Mantovani, C. Madeddu, A. Maccio, G. Gramignano, M. R. Lusso, E. Massa, G. Astara, and R. Serpe Cancer-Related Anorexia/Cachexia Syndrome and Oxidative Stress: An Innovative Approach beyond Current Treatment Cancer Epidemiol. Biomarkers Prev., October 1, 2004; 13(10): 1651 - 1659. [Abstract] [Full Text] [PDF]
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 J. F. Kelly, C. F. Elias, C. E. Lee, R. S. Ahima, R. J. Seeley, C. Bjorbaek, T. Oka, C. B. Saper, J. S. Flier, and J. K. Elmquist Ciliary Neurotrophic Factor and Leptin Induce Distinct Patterns of Immediate Early Gene Expression in the Brain Diabetes, April 1, 2004; 53(4): 911 - 920. [Abstract] [Full Text] [PDF]
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 T. Matsuki, R. Horai, K. Sudo, and Y. Iwakura IL-1 Plays an Important Role in Lipid Metabolism by Regulating Insulin Levels under Physiological Conditions J. Exp. Med., September 15, 2003; 198(6): 877 - 888. [Abstract] [Full Text] [PDF]
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J. M. Zigman and J. K. Elmquist Minireview: From Anorexia to Obesity--The Yin and Yang of Body Weight Control Endocrinology, September 1, 2003; 144(9): 3749 - 3756. [Abstract] [Full Text] [PDF]
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D. L. Marks, A. A. Butler, R. Turner, G. Brookhart, and R. D. Cone Differential Role of Melanocortin Receptor Subtypes in Cachexia Endocrinology, April 1, 2003; 144(4): 1513 - 1523. [Abstract] [Full Text] [PDF]
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 D. Hamerman Molecular-Based Therapeutic Approaches in Treatment of Anorexia of Aging and Cancer Cachexia J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2002; 57(8): M511 - 518. [Abstract] [Full Text] [PDF]
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 T. M. Reyes and P. E. Sawchenko Involvement of the Arcuate Nucleus of the Hypothalamus in Interleukin-1-Induced Anorexia J. Neurosci., June 15, 2002; 22(12): 5091 - 5099. [Abstract] [Full Text] [PDF]
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 A. Inui Cancer Anorexia-Cachexia Syndrome: Current Issues in Research and Management CA Cancer J Clin, March 1, 2002; 52(2): 72 - 91. [Abstract] [Full Text] [PDF]
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R. M. Lechan and J. B. Tatro Editorial: Hypothalamic Melanocortin Signaling in Cachexia Endocrinology, August 1, 2001; 142(8): 3288 - 3291. [Full Text] [PDF]
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B. E. Wisse, R. S. Frayo, M. W. Schwartz, and D. E. Cummings Reversal of Cancer Anorexia by Blockade of Central Melanocortin Receptors in Rats Endocrinology, August 1, 2001; 142(8): 3292 - 3301. [Abstract] [Full Text] [PDF]
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36 h in WT but
not MC4-RKO animals when expressed both as total normalized intake
(A) or as a percentage of basal (post i.p. saline)
intake (B). A, food intake after LPS.
B, percentage of basal feeding after LPS.
C, 24-h wheel turns. Normal nocturnal increase in wheel
running activity is observed in LPS-treated MC4-RKO animals (data shown
is the average turns/min in five animals, measured for 24 h,
starting at 1700 h with lights out at 1900 h).
D, weight change after LPS induction. Young MC4-RKO mice
resist LPS-induced growth failure (*, P < 0.05; **, P < 0.01
versus WT control)
