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Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Intracerebroventricular (ICV) administration of neuropeptide Y (NPY) has been shown to decrease energy expenditure, induce hypothermia, and stimulate food intake. Recent evidence has suggested that the Y5 receptor may be a significant mediator of NPY-stimulated feeding. The present study attempts to further characterize the role of NPY Y5-receptor subtypes in feeding and energy expenditure regulation. Satiated Long-Evans rats with temperature transponders implanted in the interscapular brown adipose tissue (BAT) displayed a dose-dependent decrease in BAT temperature and an increase in food intake after ICV infusion of NPY. Similar effects were induced by ICV administration of peptide analogs of NPY that activate the Y5 receptor, but not by analogs that activate Y1, Y2, or Y4 receptors. Furthermore, ICV infusion of the Y5 selective agonist D-[Trp32]-NPY significantly reduced oxygen consumption and energy expenditure of rats as measured by indirect calorimetry. These data suggest that the NPY Y5-receptor subtype not only mediates the feeding response of NPY but also contributes to brown fat temperature and energy expenditure regulation.
brown fat; hypothermia; intracerebroventricle; indirect calorimetry; obesity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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HYPOTHALAMIC NEUROPEPTIDE Y (NPY) plays a critical role in the regulation of both energy intake and energy expenditure. Numerous studies have demonstrated the potency of this 36-amino acid peptide as an orexigenic agent when administered centrally (1, 25). Central administration of NPY has also been shown to decrease sympathetic nervous system activity (9) and to suppress thermogenesis in brown adipose tissue (BAT), a primary area involved in the regulation of rodent energy expenditure (3). These coordinated effects of NPY on energy homeostasis lead to a state of positive energy balance and weight gain in the form of fat (24).
By measuring rectal body temperature, a physiological response that may reflect whole body energy expenditure, several studies reported that NPY can cause whole body hypothermia (6, 7, 20). NPY can elicit feeding responses after administration into many hypothalamic nuclei such as perifornical, ventromedial, paraventricular, arcuate, and preoptic nuclei, with the strongest effect found in the perifornical hypothalamus. In comparison, NPY-induced hypothermia can be seen after administration of the peptide into preoptic, paraventricular, and arcuate nuclei of the hypothalamus (7, 15). The fact that NPY infusion elicited only feeding but not hypothermia in the perifonical hypothalamus suggests that the feeding and hypothermic responses can be mediated by different hypothalamic nuclei (7). Bouali et al. (5) further demonstrated that the NPY-induced hypothermia was mediated by pertusis toxin-sensitive G protein-linked NPY receptor(s). However, the identity of the NPY-receptor subtypes that mediate the effects of NPY on energy homeostasis remains elusive. To date, at least six distinct G protein-linked NPY receptors have been cloned and characterized (4). With the use of in situ hybridization techniques, Y1-, Y2-, and Y5-receptor mRNA have been detected in numerous hypothalamic nuclei, including paraventricular, arcuate, and perifornical nucleus (12, 18). The pharmacological properties of the receptor subtype(s) mediating NPY-induced feeding are most similar to the pharmacological properties of the Y5 receptor (11), although the Y1 receptor also is involved in the control of feeding behavior (16, 26). The pharmacological properties of the NPY-receptor subtype(s) mediating energy expenditure regulation have not been rigorously studied. The main focus of this study is to administer NPY and its analogs by intracerebroventricular (ICV) infusion to evaluate the NPY receptor subtype(s) involved in the regulation of energy expenditure.
The discovery that BAT is an important site of thermogenesis in the rat indicates that BAT plays a significant role in modulating energy expenditure (8). Since BAT thermogenesis induces energy dissipation as heat, the change in BAT temperature may indicate relative thermogenic activities in BAT. The present study uses temperature transponders implanted in the interscapular BAT to measure the change of temperature in the BAT after ICV administration of NPY analogs. We characterized the receptor(s) mediating NPY-induced suppression of BAT temperature while concurrently measuring NPY-induced feeding behavior in free-roaming rats. To identify the receptor subtype(s) involved in NPY-mediated energy regulation, we correlated the in vitro binding and functional activities of several NPY analogs at the cloned rat Y1, Y2, Y4, and Y5 receptors with their in vivo effects on feeding and BAT temperature in ICV-cannulated rats. In addition, Y5 receptor-mediated energy expenditure regulation was studied by indirect calorimetry. Our data indicate that activation of central Y5 receptors not only increases feeding but also decreases brown fat temperature and energy expenditure in rats.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Adult male Long-Evan rats (250-300 g; Charles River, MA) were maintained in individual cages at 22°C on a 12:12-h light-dark cycle with lights on at 0400. Rats had free access to food (Teklad Lab Rodent Chow #8604, Bartonville, IL) and water. All studies were conducted in an American Association for Accreditation of Laboratory Animal Care accredited facility following protocols approved by the Animal Care and Use Committee of Schering-Plough Research Institute. The procedures were performed in accordance with the principles and guidelines established by the NIH for the care and use of laboratory animals.
Surgery. Rats were anesthetized by intramuscular injection of a mixture of ketamine and xylazine (100:10 mg/kg). A 22-gauge stainless steel cannula was stereotaxically implanted. The stereotaxic coordinates for the right lateral ventricle were obtained from the atlas of Paxinos and Watson (19). Briefly, the incisor bar was adjusted until the heights of lambda and bregma skull points were equal. This flat-skull position was achieved when the incisor bar was lowered ~3.9 mm below the interaural line. The stereotaxic coordinates for ICV cannulation were 1.0 mm posterior to bregma, 1.5 mm lateral to midline, and 2.6 mm ventral to dura, with the ICV infusion needle extended to 3.6 mm ventral to dura. Animals were also inserted with temperature transponder probes (Implantable Programmble Temperature Transponder, BioMedic Data System, Seaford, DE) in the interscapular BAT area. In some of the rats intraperitoneal telemetry temperature implants were placed in the abdominal cavity to monitor core body temperature changes. After a 3-wk recovery period, all animals were tested for cannula placement by ICV infusion of NPY (0.3 nmol). Animals demonstrating a profound feeding effect (>2.0 g) within 60 min of infusion were retained for the study.
Peptides and ICV infusion protocols.
Human (h) or rat (r) NPY, hr NPY free acid, hr NPY-(2
36), hr
NPY-(1336), h pancreatic polypeptide (PP), rPP, h peptide YY
(PYY)-(336), C2-NPY, and hD-[Trp32]-NPY were obtained
from Bachem (King of Prussia, PA). All peptides were
dissolved in 0.9% sterile saline (Sigma, St. Louis, MO) and infused
intracerebroventricularly using a Hamilton infusion pump and syringes
(Reno, NV) at a rate of 5 µl/min for 1 min. The guide cannula
remained inserted for an additional minute to prevent diffusion up the
needle track. The chow-filled feeder was weighed during the infusion
period and then returned to the home cage with the animal immediately
following treatment. BAT temperature and food consumption was monitored
at 60, 120, and 240 min after ICV infusion. Three days before each
treatment, animals were infused with saline to obtain baseline food
intake and temperature responses. Five groups of rats
(n = 5-9) received ICV infusions
of either saline or test peptide. After the study, rat brains were
fixed by 10% Formalin saline solution. Brains were sectioned, and the injection sites were determined under light microscopy. All rats having
more than 2 g of food consumption within 1 h of NPY infusion showed dye
within the cerebral ventricles.
Indirect calorimetry method. Oxygen
consumption (
O2) and carbon
dioxide production (CO2)
were monitored every 15 min (settle time: 155 s; measure time: 45 s)
for 22 h with the use of an indirect calorimeter (Oxymax, Columbus
Instruments, Columbus, OH). Measurements were taken in an airtight
Oxymax chamber (10.5 l; dimensions: 12.25 × 7.375 × 7.25 in.) with an air flow rate of 2.75 l/min. Respiratory
quotient (RQ) was calculated as the molar ratio of CO2 to
O2. Water and
food were available ad libitum in the calorimeter chamber. Percentage
of energy fuel derived from carbohydrate or fat oxidation was
determined from O2 and
CO2 using the methods of Elia and Livesey (10).
Binding and cAMP assays. The ability
of peptides to activate the various NPY-receptor subtypes and inhibit
forskolin-stimulated cAMP formation was determined as described
previously (17). CHO or HEK-293 cells expressing the various rat NPY
receptors have been described previously (17). Cells used for the
preparation of membranes for radioligand binding assays were grown and
harvested by Receptor Biology (Baltimore, MD). Briefly, cells
expressing each of the cloned NPY receptors were grown to near
confluence in 576-cm2 plates. The
cells were then scraped from the plates and centrifuged at 1,000 g for 10 min at 4°C. The resulting
cell pellets were frozen in liquid nitrogen, shipped on dry ice, and
stored at 
80°C until they were used for preparation of
membranes. Membrane preparations and receptor binding assays for each
of the cloned rat NPY receptors were carried out as described
previously (17).
Statistical analysis. Results are given as means ± SE. For each experiment, changes in temperature and food intake were analyzed using ANOVA, multiple comparisons, and paired t-test. Statistical significance of a comparison was assessed by comparing the difference in least-square means with the appropriate estimate of variability from the ANOVA. Dunnett's adjustment was used to account for multiple comparisons with the type-I error rate of 0.05 partitioned into equal amounts for comparisons within each animal type. Trends in dose response were also investigated for each response. The significance of an observed trend was assessed by the P < 0.05 of the linear contrast for dose effect from the mixed model of ANOVA.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects on binding and cAMP assays.
NPY potently binds and activates the cloned rat Y1, Y2, and Y5
receptors but is a much less effective activator of the Y4 receptor
(Table 1). Both hPP and rPP potently
activate the rat Y4 receptor in cAMP assays (Table 1), whereas hPP is
87-fold more potent than rPP in activating the rat Y5 receptors in cAMP
assays. Hence, hPP is a Y4- and Y5-receptor agonist, whereas rPP only
activates the Y4 receptors. NPY-(236) and PYY-(336) are Y2- and
Y5-receptor agonists, whereas C2-NPY and NPY-(13-36) selectively
activate the Y2 receptor (Table 1). Replacing the
Thr32 of NPY with
D-Trp completely abolishes the
Y1 and Y2 activities of NPY, while retaining some of the Y5 activity.
D-[Trp32]-NPY
is a very selective Y5 agonist, with
Ki and
EC50 values of 34 and 25 nM,
respectively, at the cloned rat Y5 receptor (Table 1).
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Effects on feeding. ICV administration
of NPY elicits robust feeding behavior in satiated cannulated rats in a
dose-dependent manner [half-maximal dose
(ED50) = 0.32 nmol;
Fig.1A].
In contrast, ICV administration of the inactive COOH-terminal free acid
form of NPY does not induce food intake in the rats (Fig.
1A) (25). The Y4- and Y5-receptor
agonist hPP also induces a dose-dependent increase of feeding behavior
(ED50 = 0.5 nmol), whereas the
Y4-selective agonist rPP did not cause any significant changes in food
intake (Fig. 1B). NPY analogs such
as NPY-(236) and PYY-(336) both stimulate food intake
(ED50 = 0.34 and 0.29 nmol,
respectively; Fig. 1C). However, the
feeding responses induced by either NPY-(1336) or the Y2-selective
agonist C2-NPY are not statistically different from that of the saline
control group (Fig. 1C). High doses
of D-[Trp32]NPY
elicit a modest but significant increase in food intake 2 h after the
ICV infusion (ED50 = 1.45 nmol;
Fig. 1D).
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Effects on brown fat temperature. With
the use of the BAT temperature transponders, we have detected a
significant increase of BAT temperature after bolus subcutaneous
injection of the 
3 agonist ICI198157, which
selectively increases brown fat thermogenesis measured by GDP binding
to BAT mitochondria (13). In cold-adapted rats, Howe et al. (13)
reported that subcutaneous injection of 15 mg/kg of ICI198157
significantly increased core body temperature. In this study, we used a
100-fold lower dose of ICI198157, which selectively increases BAT
temperature versus core body temperature (Fig.
2), suggesting that the BAT temperature
transponder can sensitively detect BAT thermogenesis in vivo. ICV
administration of NPY significantly decreases BAT temperature beginning
at 30 min postinfusion and reaching maximum at about 60 min
postinfusion. Both brown fat and core body temperature decline in a
dose-dependent manner after ICV infusion of NPY (Figs.
3 and
4A).
The selective Y4 agonist rPP did not elicit any significant changes in
brown fat temperature. In contrast, the Y4- and Y5-receptor agonist hPP
significantly reduces BAT temperature at 60 min postinfusion (Fig.
4B). NPY analogs such as NPY-(236)
and PYY-(336) both significantly lower BAT temperature 1 h after the
ICV infusion (Fig. 4C). However, the
Y2-selective agonists (C2-NPY) and NPY-(1336) did not have any effect
on BAT temperature (Fig. 4C).
Furthermore, administration
D-[Trp32]-NPY
into the lateral ventricle of rats leads to significant reduction of
BAT temperature at all doses tested (Fig.
4D).
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Effects on energy expenditure. ICV
administration of the Y5-selective agonist
D-[Trp32]-NPY
(3 nmol) causes a significant 30% decrease in
O2 and energy expenditure
compared with saline control rats during the first hour postinfusion
period (Fig. 5,
A and
B). However, the respiratory quotient of
D-[Trp32]-NPY-treated
rats is not sgnificantly different from that of the saline controls
(Fig. 5C).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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NPY modulates whole body energy balance by regulating food consumption, energy expenditure, and the metabolic processes that determine the balance between fat mobilization and storage. These physiological effects of NPY are mediated by interaction with at least six distinct G protein-coupled receptors (designated Y1-Y6) (4). The present study demonstrates that both the feeding and BAT hypothermic effects induced by central administration of NPY analogs are most consistent with activation of Y5 receptors.
Several lines of evidence from our data support the notion that central
activation of Y5 receptors not only stimulates food intake but also
decreases BAT temperature. First, ICV infusion of the Y4/Y5 agonist
hPP, but not the selective Y4 agonist rPP, stimulates feeding and BAT
hypothermia. This suggests that the Y5-derived activity of hPP is
responsible for such effects. Second, the Y2/Y5 agonists NPY-(236)
and PYY-(336) increase food intake and decrease BAT temperature.
Because the Y2 selective agonist C2-NPY has no effect on food intake or
BAT temperature, the activity of Y2 and Y5 agonists must be due to
Y5-receptor activation. Third, the Y5 selective agonist
D-[Trp32]-NPY
induces feeding and significantly reduces BAT temperature in satiated
rats. With the use of an indirect calorimetric method, we demonstrated
that immediately after central administration of a selective Y5
agonist
D-[Trp32]-NPY
(3 nmol) rats experienced a significant reduction of
O2 and energy expenditure
without affecting respiratory quotient. The transient 30% reduction of
energy expenditure correlates well with the decrease of BAT temperature
after central administration of
D-[Trp32]-NPY
and suggests that the decrease in BAT temperature partly reflects the
reduction of energy expenditure. Collectively, our data support the
hypothesis that central activation of Y5 receptor leads to increases in
food intake and decreases of BAT temperature and energy expenditure.
The lack of selective Y1 agonists precludes a fair evaluation of the
role of the Y1 receptor in feeding or BAT temperature regulation. The
fact that PYY-(336), hPP, and
D-[Trp32]-NPY
all induce feeding and BAT hypothermic effects, despite being inactive
at the cloned Y1 receptor (Table 1), suggests that Y1 receptors are not
essential for eliciting feeding and BAT hypothermic effects. However,
recent reports of Y1 and Y5 receptor knockout mice indicate that both
Y1 and Y5 receptors are involved in feeding behavior. Y5-deficient mice
had significantly lower NPY, hPP, or PYY-(336)-induced food intake
(16), whereas Y1-deficient mice showed reduced fasting-induced feeding
but not NPY-induced feeding (21). Further studies with selective
Y1-receptor agonists and antagonists will be required to determine if
activation of Y1 and Y5 receptors are both involved in NPY-dependent
energy expenditure regulation.
BAT not only plays an important role in nonshivering-induced
thermogenesis, but it also plays a significant role in diet-induced thermogenesis (22). Therefore, increasing food intake should cause BAT
hyperthermia and elevated energy expenditure. However, our study has
shown that NPY and Y5-selective peptides elicit feeding as well as BAT
hypothermia, suggesting that the BAT hypothermic effect is not
secondary to the feeding effect. The factors contributing to the BAT
hypothermia observed after central administration of NPY analogs in the
present study remain to be determined. Central administration of NPY
has been shown to decrease sympathetic nervous system activity (9). The
sympathetic nervous system modulates energy expenditure by increasing
thermogenesis through activation of 3 receptors and elevation of
uncoupling protein activity in BAT. BAT thermogenic activity is reduced
after central NPY administration (3). However, not only BAT but also
core body temperatures are both substantially reduced after central
administration of NPY in our study. Therefore, some other mechanism
such as changing regional blood flow in BAT or other subcutaneous area
(14, 28) may also contribute to the simultaneous decrease in BAT and
core body temperature.
Hypothalamic NPY plays a fundamental role in the regulation of energy balance through its orexigenic activity and profound metabolic effects. Central administration of NPY can promote a state of positive energy balance by coordinating energy intake and expenditure through the regulation of feeding and thermogenesis. Comparing the in vitro activities of selective NPY analogs with their in vivo functions, we conclude that central activation of Y5 receptors can stimulate BAT hypothermia as well as food intake. The significant 30% decrease of energy expenditure elicited by central administration of Y5-selective agonist D- [Trp32]NPY further supports the role of NPY and the Y5 receptor in the regulation of energy balance.
Perspectives
NPY plays a critical role in the successful energy regulation of normal individuals as well as the dysregulation of energy balance that characterizes obesity. For example, hypothalamic NPY peptide and mRNA levels are increased after fasting in normal rats; however, NPY mRNA levels are higher in genetically obese mice and rats without fasting (2, 23, 27). Central administration of NPY increases food intake and decreases energy expenditure in satiated rats (3, 25), suggesting that NPY can promote positive energy balance. Both Y5 and Y1 receptors seem to play an important role in the feeding behavior. The pharmacological properties of the Y5 receptor most closely correspond to the pharmacological properties of the receptor that mediates feeding induced by exogenous NPY and NPY analog (11), whereas the Y1 receptor may play a substantial role in fasting-induced feeding (21). However, the NPY-receptor subtype, which mediates the reduction of energy expenditure induced by NPY, has not been characterized. Our data indicate that central Y5-receptor activation is responsible for the observed feeding as well as the energy expenditure effects of NPY.| |
FOOTNOTES |
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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. J. Hwa, CNS/CV Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0530 (E-mail: joyce.hwa{at}spcorp.com).
Received 15 February 1999; accepted in final form 25 June 1999.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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 A. R. Kennedy, P. Pissios, H. Otu, B. Xue, K. Asakura, N. Furukawa, F. E. Marino, F.-F. Liu, B. B. Kahn, T. A. Libermann, et al. A high-fat, ketogenic diet induces a unique metabolic state in mice Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1724 - E1739. [Abstract] [Full Text] [PDF]
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K. M. Pelz and J. Dark ICV NPY Y1 receptor agonist but not Y5 agonist induces torpor-like hypothermia in cold-acclimated Siberian hamsters Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2007; 292(6): R2299 - R2311. [Abstract] [Full Text] [PDF]
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E. Keen-Rhinehart and T. J. Bartness NPY Y1 receptor is involved in ghrelin- and fasting-induced increases in foraging, food hoarding, and food intake Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1728 - R1737. [Abstract] [Full Text] [PDF]
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A. M. van den Hoek, A. C. Heijboer, P. J. Voshol, L. M. Havekes, J. A. Romijn, E. P. M. Corssmit, and H. Pijl Chronic PYY3-36 treatment promotes fat oxidation and ameliorates insulin resistance in C57BL6 mice Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E238 - E245. [Abstract] [Full Text] [PDF]
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C. Gelegen, D. A. Collier, I. C. Campbell, H. Oppelaar, and M. J. H. Kas Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E574 - E581. [Abstract] [Full Text] [PDF]
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D. E. Day, E. Keen-Rhinehart, and T. J. Bartness Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2005; 289(1): R29 - R36. [Abstract] [Full Text] [PDF]
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J. Gao, L. Ghibaudi, and J. J. Hwa Selective activation of central NPY Y1 vs. Y5 receptor elicits hyperinsulinemia via distinct mechanisms Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E706 - E711. [Abstract] [Full Text] [PDF]
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 V. Y. Polotsky, M. C. Smaldone, M. T. Scharf, J. Li, C. G. Tankersley, P. L. Smith, A. R. Schwartz, and C. P. O'Donnell Impact of interrupted leptin pathways on ventilatory control J Appl Physiol, March 1, 2004; 96(3): 991 - 998. [Abstract] [Full Text] [PDF]
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 K. Baran, E. Preston, D. Wilks, G. J. Cooney, E. W. Kraegen, and A. Sainsbury Chronic Central Melanocortin-4 Receptor Antagonism and Central Neuropeptide-Y Infusion in Rats Produce Increased Adiposity by Divergent Pathways Diabetes, January 1, 2002; 51(1): 152 - 158. [Abstract] [Full Text] [PDF]
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