Research Division, Joslin Diabetes Center and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
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ABSTRACT |
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Neuropeptide Y (NPY) is an
orexigenic (appetite-stimulating) peptide that plays an important role
in regulating energy balance. When administered directly into the
central nervous system, animals exhibit an immediate increase in
feeding behavior, and repetitive injections or chronic infusions lead
to obesity. Surprisingly, initial studies of
Npy/
mice on a mixed genetic background did
not reveal deficits in energy balance, with the exception of an
attenuation in obesity seen in ob/ob mice in which the NPY
gene was also deleted. Here, we show that, on a C57BL/6 background, NPY
ablation is associated with an increase in body weight and adiposity
and a significant defect in refeeding after a fast. This impaired
refeeding response in Npy
/
mice resulted in
a deficit in weight gain in these animals after 24 h of refeeding.
These data indicate that genetic background must be taken into account
when the biological role of NPY is evaluated. When examined on a
C57BL/6 background, NPY is important for the normal refeeding response
after starvation, and its absence promotes mild obesity.
neuropeptide Y; C57BL/6 background
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INTRODUCTION |
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FEEDING IS
REGULATED by a complex interaction between peripheral and central
signals. Peripheral signals including leptin (2, 17),
ghrelin (41), and peptide YY (3-36)
(4) are processed by key neurons in the hypothalamus. In
the central nervous system (CNS), several peptidergic systems that are
involved in feeding pathways have been identified. Orexigenic signals
such as neuropeptide Y (NPY) (13, 38) or agouti-related
peptide (AgRP) (25, 34) in the arcuate nucleus and
melanin-concentrating hormone (MCH) (23, 31, 33) in the
lateral hypothalamus all induce feeding when administered
intracerebroventricularly at pharmacological doses. Anorectic signals,
on the other hand, are primarily mediated via the melanocortin system.
For example, -melanocyte-stimulating hormone (
-MSH) and the
melanocortin receptor agonist MTII lead to decreased feeding (16,
28, 39). In addition, 5-hydroxytryptamine (serotonin) is known
to suppress appetite (7, 22, 40) via potential effects on
the melanocortin system (18).
Additional information on the role of CNS peptides has been derived
from genetic studies in which the signaling systems are disrupted.
Genetic disruption of the melanocortin system results in obesity in
both rodents and humans (20, 43). This disruption was
reported to occur at the level of the gene encoding the
proopiomelanocortin from which -MSH is processed. In addition,
slightly different obesity syndromes are seen when either of the
central melanocortin receptors MC3-R (8, 10) or MC4-R
(9) is disrupted. Results from studies on genetic
disruption of orexigenic peptides have been less consistent. Mice
lacking the gene for MCH are lean as a result of a decrease in feeding
and an increase in energy expenditure (35). Mice lacking
the MCH receptor MCHR-1 are also lean, although the primary cause of
their leanness is increased motor activity (12, 26). In
contrast, disruption of either the NPY gene or the AgRP gene does not
affect body weight or feeding behavior (14, 30), whereas
disruption of two NPY receptors, Y1 and Y5, leads to mild obesity
(21, 24, 29). Further studies indicated that NPY is
essential for the development of the full obesity syndrome in
leptin-deficient ob/ob mice (15). NPY ablation in these animals attenuated their weight gain, which supports a role
for this neuropeptide in mediating the increased adiposity in
ob/ob mice. Interestingly, a subsequent study showed that
Npy
/
mice backcrossed for two generations
onto a C57BL/6 background had an anxiogenic-like phenotype and appeared
to be hypoalgesic in a hot-plate paradigm in addition to demonstrating
a modest deficit in refeeding after starvation (3).
A potential problem with the studies reported thus far is that many of the mice analyzed were of a mixed genetic background, 129/J and C57BL/6. These two backgrounds have different sensitivities to diet-induced obesity. Hence, due to lack of genetic homogeneity in the subject mice, mixed genetic background may confound feeding studies.
To further define the role of NPY in feeding behavior, in the present study we have backcrossed subject mice at least seven generations onto a C57BL/6 background. After being backcrossed, mice were evaluated in terms of body weight, adiposity, metabolic parameters, feeding patterns, and responses to fasting.
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MATERIALS AND METHODS |
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Animals.
All studies were conducted with the approval of the Joslin Diabetes
Center Animal Care and Use Committee. The creation of Npy/
mice has been described previously
(14), and these mice were the generous gift of Dr. Richard
Palmiter, University of Washington, Seattle, WA.
Npy+/
mice were bred and backcrossed for seven
generations onto a C57BL/6 background at Taconic Farms (Germantown, NY)
and were then bred to each other to generate homozygous
Npy
/
mice and littermate wild-type (WT)
controls. Genotypes were confirmed by PCR. Mice were weaned at 3 wk of
age, genotyped, and housed in groups of 2-4 mice per cage. Animals
were given access to a diet comprised of 9% fat by weight (LabDiet
5021) and water ad libitum and were maintained in a
temperature-controlled room (24°C) under an alternating 12:12-h
light-dark cycle.
Fasting/refeeding groups of studies. Groups of 20-wk-old mice were fasted for a period of 24 h starting at the beginning of the light cycle. At the end of the fast, preweighed food was reintroduced, and food intake was monitored for 1, 3, 6, 24, and 48 h. Body weight was measured before and immediately after the fast as well as 6, 24, and 48 h after refeeding.
Restricted-feeding paradigm.
Mice were placed on a restricted-feeding paradigm as previously
described (1). Six 4-mo-old male
Npy/
mice and seven age-matched WT controls
were allowed limited access to food for only 4 h during the light
cycle, between 1100 and 1500, for a period of 18 days. Body weights
were recorded on a daily basis just before the animals received food.
Mice were given a preweighed amount of food, and food intake was
measured daily at the end of the 4-h feeding period.
Indirect calorimetry.
Metabolic rate was measured for four 28-wk-old female
Npy/
mice and four WT control mice. These
animals were those previously used at 20 wk of age for the manual
fasting/refeeding study described earlier. Metabolic rate was measured
by indirect calorimetry using an eight-chamber open-circuit Oxymax
system component of the Comprehensive Lab Animal Monitoring System
(CLAMS; Columbus Instruments, Columbus, OH). Mice were maintained at
~24°C under a 12:12-h light-dark cycle (light period
0800-2000). Food and water were available ad libitum except where
noted below. Animals were individually housed in specially built
Plexiglas cages (5 × 4.5 × 8.5 in.), through which room air
was passed at a flow rate of ~0.54 l/min. Exhaust air from each
chamber was sampled at 1-h intervals for a period of 1 min. Sample air
was sequentially passed through O2 and CO2
sensors (Columbus Instruments) for determination of O2 and
CO2 content. All mice were acclimatized to the cage for 24 h before hourly recordings of physiological parameters
commenced. Mice then underwent a 3-day course in the CLAMS: 24 h
fed, 24 h fasted, and 24 h refed. Mice were weighed before
each trial.
Food intake and diet composition.
During acclimation and testing periods, female
Npy/
mice (n = 4; 28.6 g mean body wt) and WT littermates (n = 4; 26.5 g
mean body wt) were individually housed in microisolation cages and maintained on milled Labdiet 5021 (9% fat by weight) under a light cycle from 0800 to 2000. During CLAMS monitoring, feeding was assessed
using ground food placed in eight acrylic side feeders, each attached
to a microisolation cage. Side feeders rested on balances directly
linked to a computer for measuring continuous food intake. During each
one of the feeding periods, cumulative food intake was automatically
recorded every hour for 24 h.
Motor activity. Ambulatory activity of individually housed mice was evaluated within the metabolic chambers on a relative basis using an eight-cage rack OPTO-M3 sensor system (Columbus Instruments). Consecutive photobeam breaks occurring in adjacent photobeams were scored as an ambulatory movement. Cumulative ambulatory activity counts were recorded every hour throughout the light and dark cycles.
Body fat measurement.
Eight-mo-old male Npy/
and age-matched WT
littermate controls were analyzed using dual-energy X-ray
absorptiometry (DEXA; Lunar PIXImus2 mouse densitometer; GE Medical
systems, Madison WI) as described by the manufacturer. Briefly, the
machine was calibrated daily using a phantom provided by the
manufacturer. The system has an image acquisition time of <5 min. The
interassay coefficient of variation was 0.22%. Before being scanned,
mice were intraperitoneally injected with a (1:1) mixture of
tribromoethanol and tert-amyl alcohol (15 µl/g body wt),
and an in vivo prediction of fat content was subsequently performed.
Statistics. Values are reported as group means ± SE. Interactions between genotype and physiological parameters across light and dark cycles were analyzed by one-way ANOVA (factorial) when appropriate. The level of significance was taken as P < 0.05. Statistical comparisons were made using Statview (Abacus Concepts, Berkley, CA) software.
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RESULTS |
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Body weights.
Weights of both male and female Npy/
mice
vs. their respective WT counterparts were monitored on a weekly basis
beginning from 3 wk of age until the animals were 17 wk old. As shown
in Fig. 1A, both male
Npy
/
mice and male WT animals exhibited
similar body weights up to 11 wk of age. However, from week
12 onward, male Npy
/
mice exhibited a
significantly higher body weight than their WT counterparts. At 12 wk,
male Npy
/
mice weighed 29.14 ± 0.7 vs.
27.07 ± 0.5 g for WT males (P = 0.016), and
this difference in body weight was maintained through week
17. A similar trend was observed for female
Npy
/
mice compared with their WT
counterparts (Fig. 1B). Both Npy
/
and WT females showed similar weights up to 14 wk of age. However, by
week 15, female Npy
/
mice weighed
24.76 ± 1.5 vs. 22.06 ± 0.7 g for female WT animals (P = 0.03), and this increase in body weight was also
maintained through week 17. Npy
/
females were further followed up to 37 wk of age and at this later time
point still weighed significantly more than their WT counterparts
(39.83 ± 1.52 vs. 30.38 ± 1.11 g, respectively,
P = 0.0005; Fig. 1B). Thus, on a C57BL/6
background, both male and female Npy
/
mice
exhibited increased body weights compared with WT mice.
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Body fat composition.
To further define the role of NPY in body weight composition, the
percentage of total body fat was measured in four 32-wk-old male
Npy/
and WT controls by DEXA scanning. As
depicted in Fig. 2,
Npy
/
mice had significantly higher total
percent body fat compared with WT animals (40.87 ± 0.7 vs.
37.22 ± 0.7% respectively). In parallel, we also determined the
percentage of lean body mass for these animals. The percent lean body
mass for Npy
/
mice was 59.12 ± 0.7%,
whereas that for WT animals was 62.77 ± 0.7% (P = 0.012).
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Fasting/refeeding.
Under normal conditions, Npy/
and WT mice
have similar food intakes, with 20-wk-old animals from both groups
consuming ~3.4 g of chow per day. To determine the effects, if any,
of Npy ablation on refeeding after a prolonged fast,
Npy
/
male and female mice and their WT
counterparts were fasted for 24 h (from the beginning of one light
cycle to the beginning of the light cycle on the successive day). After
being fasted, animals were subsequently allowed to refeed ad libitum,
and short-term food intake was measured for
6 h. In addition, food
intake was determined over more prolonged intervals of 24 and 48 h. After being fasted for 24 h, all animals increased their food
intake compared with their baseline intake; however, female
Npy
/
mice ate significantly less than their
WT counterparts (Fig. 3, A and
B). This reduced refeeding
behavior manifested itself as early as 1 h after the animals were
allowed to refeed [0.9 ± 0.05 (WT) vs. 0.4 ± 0.07 g
(Npy
/
), P < 0.0001] and
persisted up to the 48-h time point [11.6 ± 0.06 (WT) vs.
9.4 ± 0.08 g (Npy
/
),
P < 0.0001]. The greatest disparity in food intake
was observed during the first 6 h of refeeding, during which WT
mice ate more than twice as much as Npy
/
mice. A similar pattern was observed for male
Npy
/
mice vs. their WT counterparts.
However, the reduced food intake in male
Npy
/
mice did not reach statistical
significance (data not shown).
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Restricted feeding.
To further examine the effect of NPY ablation on the response to
altered food availability, we utilized a restricted-feeding paradigm
(1). Four-month-old Npy/
and WT
mice were allowed access to food only during the light cycle, between
1100 and 1500. Neither normal nor NPY-ablated mice were able to fully
adapt to the timed feeding (Fig. 5). Food
intake during the first 24 h fell below 1 g in both groups
(Fig. 5A). Food intake began to increase on the 2nd day, but
Npy
/
animals lagged behind WT animals until
day 11, when feeding curves overlapped. Subsequently, both
sets of animals continued to slowly increase food intake toward normal
(Fig. 5A). Over the first 4 days, both control and
Npy
/
animals lost 15% of their initial body
weight (Fig. 5B). The Npy
/
mice
lost correspondingly more weight, and their weights finally stabilized
at a lower level compared with control mice (Fig. 5B).
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Metabolic analysis of
Npy/
mice.
To further characterize potential defects in energy balance resulting
from NPY ablation, the metabolic rates for both WT and Npy
/
animals were determined by indirect
calorimetry using a CLAMS apparatus. Acclimated animals underwent a
3-day regimen in the CLAMS consisting of 24-h feeding, 24-h fasting,
and 24-h refeeding. Oxygen consumption
(
O2), when corrected for body
weight, was the same in both Npy
/
and WT
mice during fed, fasted, and refed phases; in both sets of animals,
O2 dropped significantly during the
fasted interval and rose with refeeding (Fig.
6). Simultaneously, the respiratory exchange ratio (RER) was calculated as an index of carbohydrate and
lipid metabolism. As shown in Fig. 7,
A and B, the RER for both WT and
Npy
/
mice was the same during both fed and
fasted phases. However, during the first 9 h of refeeding,
Npy
/
mice exhibited a marked reduction in
RER compared with WT mice (Fig. 7C). This indicates that,
during the first 9 h of refeeding, compared with WT mice,
Npy
/
mice utilized lipids to a greater
extent than carbohydrates as a source of oxidizable substrates. To rule
out differences in locomotor activity as an underlying cause for the
late-onset obesity observed in Npy
/
mice
compared with their WT counterparts, their activity was evaluated. As
shown in Fig. 8, locomotor activity was
reduced for both animal groups in the fasted state compared with either the fed or refed states. However, no difference in activity was observed between Npy
/
mice and WT animals.
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DISCUSSION |
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NPY appears to be an important regulator of energy balance. When administered intracerebroventricularly to rats, it leads to a robust induction of food intake. Furthermore, chronic infusion of NPY leads to increased adiposity and insulin resistance as well as to a decrease in basal energy expenditure (6, 27, 44). Interestingly, reports to date indicate that mice lacking NPY show no abnormality in terms of weight, food intake, or energy expenditure (5, 14, 27). Similarly, a recent study showed that mice lacking both NPY and AgRP have no obvious feeding or body weight deficits and have a normal response to starvation (30). However, NPY ablation in leptin-deficient ob/ob mice attenuated their obesity (15), indicating that increased NPY production induced by leptin deficiency in the ob/ob mouse contributes to the increased adiposity seen in this model.
In addition, a previous study reported that, compared with WT animals,
Npy/
mice backcrossed for two generations
onto a C57BL/6 background had a diminished response to refeeding after
a prolonged fast (3). In that study, the authors reported
a 25% reduction in food intake after a fast by
Npy
/
mice compared with their WT
counterparts. Our study confirms these findings and shows an even
greater reduction in postfast food intake of up to 50% for the
Npy
/
mice compared with their WT
counterparts. The differences between the study performed by Bannon et
al. (3) and our study, in terms of the magnitude of the
refeeding deficit in Npy
/
mice, may stem
from the different degree of backcrossing of the animals in the two
studies. Furthermore, the timing of the refed interval in the former
study is unclear. If refeeding took place at the beginning of the dark
cycle, this could potentially explain the lower magnitude of the
refeeding deficit obseved in Npy
/
mice by
Bannon et al. Similarly, other data suggest that NPY deficiency
attenuates the hyperphagia seen with streptozotocin-induced diabetes
(36). In aggregate, these data suggest that the absence of
NPY may attenuate certain obese phenotypes and also cause subtle changes in feeding under conditions where hyperphagia is expected.
Genetic background plays an important role in energy balance and may
affect the susceptibility of an animal to diet-induced obesity. For
example, mice on a C57BL/6 background are more prone to becoming obese
when placed on a high-fat diet than mice on a 129 background (32,
37). Most knockout mouse strains, including Npy/
mice, are on a mixed 129 × C57BL/6 background. When Npy
/
mice were
analyzed on this background, no differences were detected compared with
WT mice in terms of body weight, basal food intake, and food intake in
response to fasting (14), and it is possible that the
mixed background may have obscured differences in energy balance.
In the present study, we reevaluated the phenotype of
Npy/
mice by utilizing animals backcrossed
for seven generations onto a C57BL/6 background. We wanted to further
explore the possibility that Npy
/
mice have
an energy homeostasis deficit that may be masked on a mixed genetic
background. Interestingly, we found that these mice exhibited mild
obesity beginning at 12-13 wk of age. Under normal conditions, we
did not observe differences in food intake between
Npy
/
and WT mice. However, our methodology
is inadequate for measuring small changes in food intake, and it is
possible that a small increase in feeding over time in
Npy
/
mice is responsible for their mild
obesity. The obesity in our Npy
/
mice was
associated with a small but statistically significant increase in total
body fat as well as a decrease in lean body mass, leading to an
alteration in the ratio of lean body mass to fat body mass. It should
be noted that a similar increase in weight with no apparent change in
food intake was also reported for Y1r- and
Y5r-null mice (21, 29, 42). Thus the absence of
either NPY ligand or its cognate receptors may lead to mild obesity.
The mechanisms underlying this effect remain unclear and will be the
subject of future studies.
We also found a significant deficit in refeeding after a 24-h fast when
the fast was timed to begin and end at the onset of the light cycle.
This effect was initially measured manually but was more dramatically
demonstrated in mice studied in metabolic chambers. When food was
returned to mice fasted for 24 h at the onset of the light cycle,
WT mice immediately began eating at an accelerated rate, whereas
Npy/
mice ate at the rate of nonfasted
animals. This failure to refeed adequately was associated with a
persistent decrease in the RER, indicating that the mice were still in
negative caloric balance and were preferentially utilizing fat for
fuel. When the fasting and subsequent refeeding phases were initiated
at the beginning of the dark cycle, the deficit in refeeding was not as
dramatic and was consistent with the refeeding deficit previously
reported (3). These data indicate that the refeeding
response to a fast is mediated, at least in part, by upregulation and
increased secretion of NPY in the hypothalamus (19).
However, the data also indicate that environmental cues such as ambient
light are important in initiating feeding and are likely to be
reinforced by circadian changes in other hormones and neuropeptides
that signal "feeding time." In the absence of environmental and
circadian cues, the lack of NPY leads to a failure in the refeeding
response. To confirm that the reduced refeeding in
Npy
/
mice was not related to the slight
increase in their adiposity, this experiment was repeated in
weight-matched animals, and the same impairment was noted for both male
and female Npy
/
mice. To evaluate the
chronic response of Npy
/
mice to
altered food availability, a restricted-feeding paradigm was
utilized. Under this regimen, mice chronically fasted for 20 h and
subsequently allowed to refeed only during a 4-h window in the light
phase also exhibited a postfast refeeding impairment over a period of
several days. It is somewhat paradoxical that impairment of NPY
signaling, either at the level of the ligand or at the level of the
receptor (Y1R and Y5R), leads to obesity despite a postfast refeeding
deficit. Currently, the basis for this observation remains unclear.
However, these findings suggest that refeeding after a fast and the
maintenance of body weight under normal conditions may be regulated by
different central pathways. Interestingly, unlike
Npy
/
animals, mice lacking another
orexigenic peptide, MCH, on either a mixed (35) or a pure
C57BL/6 genetic background (E. Maratos-Flier, unpublished
observations), do not show a postfast refeeding deficit, suggesting
that the role of NPY in mediating food-seeking behavior after a fast is
relatively specific.
O2, carbon dioxide production, and
activity in Npy
/
mice were the same as those
of controls in the fed, fasted, and refed states. Both gas exchange and
activity decreased significantly in both groups of mice when animals
were fasted, declining to levels that were 50% of those seen in the
fed state. It should be noted that the gas measurements are adjusted
for body weight (Vgas · kg
1 · h
1).
There is some debate as to the best method for reporting
O2; however, it should be noted
that, without the weight adjustment, Npy
/
mice would have shown a 10% increase in
O2. This slight increase in
metabolic rate is expected, given the known pharmacological effect of
NPY to reduce metabolic rate (27). Similarly, RER was the
same in both WT and Npy
/
animals except for
the first 12 h of the refed state. The lower RER observed in
Npy
/
mice during the first 9 h of
refeeding after a 24-h fast reflects a continued reliance on fat as a
fuel, given their inability to ingest sufficient carbohydrates as a
source of fuel during the refeeding interval.
In both the fed and fasted states, a distinct diurnal variation in
activity was seen. In contrast, in WT animals, the diurnal cycle was
disrupted, as refed WT animals showed an increase in activity during
the light cycle related to compensatory feeding. This increase in
activity observed in WT but not in Npy/
mice
as food was reintroduced may reflect a difference in motivation to seek
food after a fast. Although WT mice seemed to be aroused by the
reintroduction of food, Npy
/
mice appeared
to be much less stimulated by its presence.
In summary, these results indicate that NPY ablation on a C57BL/6 background leads to increased body weight despite apparently normal food intake as well as to a diminished refeeding response to starvation. Taken together, these findings further underscore the importance of NPY in regulating energy balance, in particular in mediating refeeding responses after a prolonged period of food deprivation
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ACKNOWLEDGEMENTS |
---|
We thank Dr. Richard Palmiter for generously providing the
Npy/
mice and for many helpful suggestions.
We also thank Dr. Richard L. Bradley for helpful discussions, and Elena
Nikiforova for valuable assistance on the manuscript.
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FOOTNOTES |
---|
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1 DK-56116 and RO1 DK-53978 to E. Maratos-Flier. E. Maratos-Flier is also a Principal Investigator on Program Project DK-56113.
Address for reprint requests and other correspondence: E. Maratos-Flier, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215 (E-mail: emf1{at}joslin.harvard.edu).
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. Section 1734 solely to indicate this fact.
First published February 11, 2003;10.1152/ajpendo.00491.2002
Received 11 November 2002; accepted in final form 9 February 2003.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Ahima, RS,
Prabakaran D,
and
Flier JS.
Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function.
J Clin Invest
101:
1020-1027,
1998
2.
Ahima, RS,
Prabakaran D,
Mantzoros C,
Qu D,
Lowell B,
Maratos-Flier E,
and
Flier JS.
Role of leptin in the neuroendocrine response to fasting.
Nature
382:
250-252,
1996[ISI][Medline].
3.
Bannon, AW,
Seda J,
Carmouche M,
Francis JM,
Norman MH,
Karbon B,
and
McCaleb ML.
Behavioral characterization of neuropeptide Y knockout mice.
Brain Res
868:
79-87,
2000[ISI][Medline].
4.
Batterham, RL,
Cowley MA,
Small CJ,
Herzog H,
Cohen MA,
Dakin CL,
Wren AM,
Brynes AE,
Low MJ,
Ghatei MA,
Cone RD,
and
Bloom SR.
Gut hormone PYY(3-36) physiologically inhibits food intake.
Nature
418:
650-654,
2002[ISI][Medline].
5.
Beck, B.
KO's and organisation of peptidergic feeding behavior mechanisms.
Neurosci Biobehav Rev
25:
143-158,
2001[ISI][Medline].
6.
Beck, B,
Stricker-Krongrad A,
Nicolas JP,
and
Burlet C.
Chronic and continuous intracerebroventricular infusion of neuropeptide Y in Long-Evans rats mimics the feeding behaviour of obese Zucker rats.
Int J Obes Relat Metab Disord
16:
295-302,
1992[Medline].
7.
Blundell, JE.
Serotonin and appetite.
Neuropharmacology
23:
1537-1551,
1984[ISI][Medline].
8.
Butler, AA,
Kesterson RA,
Khong K,
Cullen MJ,
Pelleymounter MA,
Dekoning J,
Baetscher M,
and
Cone RD.
A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.
Endocrinology
141:
3518-3521,
2000
9.
Butler, AA,
Marks DL,
Fan W,
Kuhn CM,
Bartolome M,
and
Cone RD.
Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat.
Nat Neurosci
4:
605-611,
2001[ISI][Medline].
10.
Chen, AS,
Marsh DJ,
Trumbauer ME,
Frazier EG,
Guan XM,
Yu H,
Rosenblum CI,
Vongs A,
Feng Y,
Cao L,
Metzger JM,
Strack AM,
Camacho RE,
Mellin TN,
Nunes CN,
Min W,
Fisher J,
Gopal-Truter S,
MacIntyre DE,
Chen HY,
and
Van der Ploeg LH.
Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.
Nat Genet
26:
97-102,
2000[ISI][Medline].
11.
Chen, AS,
Metzger JM,
Trumbauer ME,
Guan XM,
Yu H,
Frazier EG,
Marsh DJ,
Forrest MJ,
Gopal-Truter S,
Fisher J,
Camacho RE,
Strack AM,
Mellin TN,
MacIntyre DE,
Chen HY,
and
Van der Ploeg LH.
Role of the melanocortin-4 receptor in metabolic rate and food intake in mice.
Transgenic Res
9:
145-154,
2000[ISI][Medline].
12.
Chen, Y,
Hu C,
Hsu CK,
Zhang Q,
Bi C,
Asnicar M,
Hsiung HM,
Fox N,
Slieker LJ,
Yang DD,
Heiman ML,
and
Shi Y.
Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity.
Endocrinology
143:
2469-2477,
2002
13.
Clark, JT,
Kalra PS,
Crowley WR,
and
Kalra SP.
Neuropeptide Y and human pancreatic polypetide stimulate feeding behavior in rats.
Endocrinology
115:
427-429,
1984[Abstract].
14.
Erickson, JC,
Clegg KE,
and
Palmiter RD.
Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.
Nature
381:
415-421,
1996[ISI][Medline].
15.
Erickson, JC,
Hollopeter G,
and
Palmiter RD.
Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.
Science
274:
1704-1707,
1996
16.
Fan, W,
Boston BA,
Kesterson RA,
Hruby VJ,
and
Cone RD.
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.
Nature
385:
165-168,
1997[ISI][Medline].
17.
Friedman, JM,
and
Halaas JL.
Leptin and the regulation of body weight in mammals.
Nature
395:
763-770,
1998[ISI][Medline].
18.
Heisler, LK,
Cowley MA,
Tecott LH,
Fan W,
Low MJ,
Smart JL,
Rubinstein M,
Tatro JB,
Marcus JN,
Holstege H,
Lee CE,
Cone RD,
and
Elmquist JK.
Activation of central melanocortin pathways by fenfluramine.
Science
297:
609-611,
2002
19.
Kalra, SP,
Dube MG,
Sahu A,
Phelps CP,
and
Kalra PS.
Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food.
Proc Natl Acad Sci USA
88:
10931-10935,
1991[Abstract].
20.
Krude, H,
Biebermann H,
Luck W,
Horn R,
Brabant G,
and
Gruters A.
Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans.
Nat Genet
19:
155-157,
1998[ISI][Medline].
21.
Kushi, A,
Sasai H,
Koizumi H,
Takeda N,
Yokoyama M,
and
Nakamura M.
Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice.
Proc Natl Acad Sci USA
95:
15659-15664,
1998
22.
Leibowitz, SF,
and
Shor-Posner G.
Brain serotonin and eating behavior.
Appetite
7:
1-14,
1986[ISI][Medline].
23.
Ludwig, DS,
Mountjoy KG,
Tatro JB,
Gillette JA,
Frederich RC,
Flier JS,
and
Maratos-Flier E.
Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.
Am J Physiol Endocrinol Metab
274:
E627-E633,
1998
24.
Marsh, DJ,
Hollopeter G,
Kafer KE,
and
Palmiter RD.
Role of the Y5 neuropeptide Y receptor in feeding and obesity.
Nat Med
4:
718-721,
1998[ISI][Medline].
25.
Marsh, DJ,
Miura GI,
Yagaloff KA,
Schwartz MW,
Barsh GS,
and
Palmiter RD.
Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues.
Brain Res
848:
66-77,
1999[ISI][Medline].
26.
Marsh, DJ,
Weingarth DT,
Novi DE,
Chen HY,
Trumbauer ME,
Chen AS,
Guan XM,
Jiang MM,
Feng Y,
Camacho RE,
Shen Z,
Frazier EG,
Yu H,
Metzger JM,
Kuca SJ,
Shearman LP,
Gopal-Truter S,
MacNeil DJ,
Strack AM,
MacIntyre DE,
Van der Ploeg LH,
and
Qian S.
Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism.
Proc Natl Acad Sci USA
99:
3240-3245,
2002
27.
Menendez, JA,
McGregor IS,
Healey PA,
Atrens DM,
and
Leibowitz SF.
Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus.
Brain Res
516:
8-14,
1990[ISI][Medline].
28.
Murphy, B,
Nunes CN,
Ronan JJ,
Harper CM,
Beall MJ,
Hanaway M,
Fairhurst AM,
Van der Ploeg LH,
MacIntyre DE,
and
Mellin TN.
Melanocortin mediated inhibition of feeding behavior in rats.
Neuropeptides
32:
491-497,
1998[ISI][Medline].
29.
Pedrazzini, T,
Seydoux J,
Kunstner P,
Aubert JF,
Grouzmann E,
Beermann F,
and
Brunner HR.
Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor.
Nat Med
4:
722-726,
1998[ISI][Medline].
30.
Qian, S,
Chen H,
Weingarth D,
Trumbauer ME,
Novi DE,
Guan X,
Yu H,
Shen Z,
Feng Y,
Frazier E,
Chen A,
Camacho RE,
Shearman LP,
Gopal-Truter S,
MacNeil DJ,
Van der Ploeg LH,
and
Marsh DJ.
Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice.
Mol Cell Biol
22:
5027-5035,
2002
31.
Qu, D,
Ludwig DS,
Gammeltoft S,
Piper M,
Pelleymounter MA,
Cullen MJ,
Mathes WF,
Przypek R,
Kanarek R,
and
Maratos-Flier E.
A role for melanin-concentrating hormone in the central regulation of feeding behaviour.
Nature
380:
243-247,
1996[ISI][Medline].
32.
Rebuffe-Scrive, M,
Surwit R,
Feinglos M,
Kuhn C,
and
Rodin J.
Regional fat distribution and metabolism in a new mouse model (C57BL/6J) of non-insulin-dependent diabetes mellitus.
Metabolism
42:
1405-1409,
1993[ISI][Medline].
33.
Rossi, M,
Choi SJ,
O'Shea D,
Miyoshi T,
Ghatei MA,
and
Bloom SR.
Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight.
Endocrinology
138:
351-355,
1997
34.
Rossi, M,
Kim MS,
Morgan DG,
Small CJ,
Edwards CM,
Sunter D,
Abusnana S,
Goldstone AP,
Russell SH,
Stanley SA,
Smith DM,
Yagaloff K,
Ghatei MA,
and
Bloom SR.
A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.
Endocrinology
139:
4428-4431,
1998
35.
Shimada, M,
Tritos NA,
Lowell BB,
Flier JS,
and
Maratos-Flier E.
Mice lacking melanin-concentrating hormone are hypophagic and lean.
Nature
396:
670-674,
1998[ISI][Medline].
36.
Sindelar, DK,
Mystkowski P,
Marsh DJ,
Palmiter RD,
and
Schwartz MW.
Attenuation of diabetic hyperphagia in neuropeptide Y-deficient mice.
Diabetes
51:
778-783,
2002
37.
Surwit, RS,
Feinglos MN,
Rodin J,
Sutherland A,
Petro AE,
Opara EC,
Kuhn CM,
and
Rebuffe-Scrive M.
Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice.
Metabolism
44:
645-651,
1995[ISI][Medline].
38.
Tomaszuk, A,
Simpson C,
and
Williams G.
Neuropeptide Y, the hypothalamus and the regulation of energy homeostasis.
Horm Res
46:
53-58,
1996[ISI][Medline].
39.
Vergoni, AV,
and
Bertolini A.
Role of melanocortins in the central control of feeding.
Eur J Pharmacol
405:
25-32,
2000[ISI][Medline].
40.
Weiss, GF,
Papadakos P,
Knudson K,
and
Leibowitz SF.
Medial hypothalamic serotonin: effects on deprivation and norepinephrine-induced eating.
Pharmacol Biochem Behav
25:
1223-1230,
1986[ISI][Medline].
41.
Wren, AM,
Small CJ,
Ward HL,
Murphy KG,
Dakin CL,
Taheri S,
Kennedy AR,
Roberts GH,
Morgan DG,
Ghatei MA,
and
Bloom SR.
The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.
Endocrinology
141:
4325-4328,
2000
42.
Wyss, P,
Stricker-Krongrad A,
Brunner L,
Miller J,
Crossthwaite A,
Whitebread S,
and
Criscione L.
The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes.
Regul Pept
75-76:
363-371,
1998.
43.
Yaswen, L,
Diehl N,
Brennan MB,
and
Hochgeschwender U.
Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.
Nat Med
5:
1066-1070,
1999[ISI][Medline].
44.
Zarjevski, N,
Cusin I,
Vettor R,
Rohner-Jeanrenaud F,
and
Jeanrenaud B.
Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity.
Endocrinology
133:
1753-1758,
1993[Abstract].