(Hypertension. 1999;33:542-547.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Interactions Between the Melanocortin System and Leptin in Control of Sympathetic Nerve Traffic
From the Hypertension Genetics Specialized Center of Research, Cardiovascular Center, and Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa.
Correspondence to William G. Haynes, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail william-g-haynes{at}uiowa.edu
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Abstract |
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Abstract—Leptin plays an important role in regulation of body weight through regulation of food intake and sympathetically mediated thermogenesis. The hypothalamic melanocortin system, via activation of the melanocortin-4 receptor (MC4-R), decreases appetite and weight, but its effects on sympathetic nerve activity (SNA) are unknown. In addition, it is not known whether sympathoactivation to leptin is mediated by the melanocortin system. We tested the interactions between these systems in regulation of brown adipose tissue (BAT) and renal and lumbar SNA in anesthetized Sprague-Dawley rats. Intracerebroventricular administration of the MC4-R agonist MT-II (200 to 600 pmol) produced a dose-dependent sympathoexcitation affecting BAT and renal and lumbar beds. This response was completely blocked by the MC4-R antagonist SHU9119 (30 pmol ICV). Administration of leptin (1000 µg/kg IV) slowly increased BAT SNA (baseline, 41±6 spikes/s; 6 hours, 196±28 spikes/s; P=0.001) and renal SNA (baseline, 116±16 spikes/s; 6 hours, 169±26 spikes/s; P=0.014). Intracerebroventricular administration of SHU9119 did not inhibit leptin-induced BAT sympathoexcitation (baseline, 35±7 spikes/s; 6 hours, 158±34 spikes/s; P=0.71 versus leptin alone). However, renal sympathoexcitation to leptin was completely blocked by SHU9119 (baseline, 142±17 spikes/s; 6 hours, 146±25 spikes/s; P=0.007 versus leptin alone). This study demonstrates that the hypothalamic melanocortin system can act to increase sympathetic nerve traffic to thermogenic BAT and other tissues. Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system.
Key Words: autonomic nervous system • renal nerves • sympathetic nervous system • brain • obesity • leptin
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Introduction |
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Recent studies of monogenic animal models of obesity have implicated several molecular mechanisms responsible for body weight control. These factors include leptin,1 neuropeptide Y (NPY),2 3 corticotrophin-releasing factor,4 and the melanocortin system.5 6 Abnormalities in these systems produce obesity through changes in appetite and food intake. In addition, leptin, neuropeptide Y, and corticotrophin-releasing factor have been shown to influence sympathetic nerve activity (SNA) to brown adipose tissue (BAT), thereby increasing thermogenesis.7 8 9 In the neural melanocortin system that controls body weight,
-melanocyte–stimulating hormone (-MSH)
derived from proopiomelanocortin (POMC) acts on melanocortin-4
receptors (MC4-Rs) to decrease appetite.5 6 Obesity in
humans has recently been linked to the POMC and MC4-R
genes.10 11 12 Melanocortin agonists have been shown to
inhibit appetite, but the effects of the melanocortin system on SNA to
thermogenic and nonthermogenic tissues are not known. One purpose of
this study was to examine the effects of the melanocortin-3 and
melanocortin-4 receptor (MC3/4-R) agonist
MT-II—Ac-Nle4-c[Asp5,D-Phe7,Lys10]-MSH-(4–10)-NH213
on SNA to BAT, hind limb, and kidney. We tested the specificity of
responses for the melanocortin system by using the MC3/4-R
antagonist
SHU9119—Ac-Nle4-c[Asp5,D-2'Nal7,Lys10]-MSH-(4–10)-NH2.13
Abnormalities in the melanocortin system are known to underlie
obesity in the agouti murine obesity syndrome.5 6 14 These
mice produce an endogenous antagonist of the
hypothalamic MC4-R that blocks the suppression of feeding by -MSH.
Agouti mice are leptin resistant,15 leading to the
suggestion that stimulation of the MC4-R by melanocortins is an
essential mechanism in the actions of leptin. However, double-mutant
leptin-deficient obese mice that also possess the agouti mutation are
more obese than mice with leptin deficiency alone, suggesting that the
melanocortin system does not play a role in the effects of leptin on
body weight.16 The role of MC4-R in the sympathetic
effects of leptin has not been reported. We examined the contribution
of the hypothalamic melanocortin system in sympathoexcitation to leptin
using third cerebral ventricle administration of the MC3/4-R
antagonist SHU9119.6 13
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Methods |
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General
All procedures were approved by the University of Iowa and Iowa City Veterans Affairs Animal Research committees. Experiments were performed in free-feeding 3-month-old male Sprague-Dawley rats (300 to 310 g) from Harlan Sprague Dawley Inc (Indianapolis, Ind). Unless otherwise indicated, all procedures were performed as previously reported.9
Procedures
Rats were anesthetized with pentobarbital (Nembutal, 50
mg/kg IP) and secured in a Kopf 900 stereotaxic instrument
(David Kopf Instruments) as described previously.17
Briefly, a 23-gauge stainless steel guide cannula (16 mm in
length) was lowered 10° from vertical into the third ventricle
according to standard stereotaxic procedures. The
coordinates with respect to bregma were -1.0 mm anteroposterior,
1.5 mm lateral from the midline, and -9.0 mm dorsoventral
from the dura. Placements of the cannula in the third ventricle were
considered patent by the acute drinking responses of >4.0 mL to
carbachol injection (50 ng ICV).17
Intracerebroventricular injections were
made in a volume of 20 µL and given over 10 minutes. Brains were
stained and stored in 10% formalin, and the correct placement of the
cannula was confirmed by microtome slicing. Arterial
pressure and direct multifiber recordings of SNA to BAT,
kidney, and hind limb were measured as described
previously.9 18
Design
Studies were performed at least 7 days after placement of the
third ventricle catheter. Animals were allowed to stabilize for 45
minutes after placement of nerve electrodes. Baseline measurements of
arterial pressure, heart rate, and SNA were made
continuously for 30 minutes. After administration of experimental
agents, hemodynamic and SNA measurements were made
every 5 minutes for 360 minutes. Arterial blood glucose
concentrations were measured at baseline and every 30 minutes
thereafter. Terminally, rats were euthanized, and any remaining nerve
activity was used to estimate background noise. Two protocols were
followed.
Role of Melanocortin Receptors in Regulation of Sympathetic
Nerve Traffic
Rats instrumented for measurement of BAT and renal SNA received
intracerebroventricular injection of
vehicle (phosphate-buffered saline; n=12) or the MC3/4-R agonist MT-II
(Ki at MC4-R, 6.6 nmol/L) in doses of 200
(n=11), 400 (n=12), and 600 (n=12) pmol. Other rats received the
MC3/4-R antagonist SHU9119 (Ki
at MC4-R, 0.36 nmol/L) either alone (30 pmol; n=4) or followed 10
minutes later by MT-II (600 pmol; n=6). Rats instrumented for
measurement of lumbar SNA received either
intracerebroventricular vehicle (n=10)
or MT-II (600 pmol; n=16).
Role of Melanocortin Receptors in Sympathoexcitation to
Leptin
Rats instrumented for measurement of BAT and renal SNA received
intracerebroventricular injection of
vehicle (n=11) or the MC3/4-R antagonist SHU9119 (30 pmol;
n=12). All rats then received murine leptin (1000 µg/kg IV over 3
hours; Amgen Inc) as a 500-µg/kg loading dose over 10 minutes
followed by an infusion at 167 µg ·
kg-1 · h-1. This
regimen results in a rapid and sustained increase in plasma leptin
concentrations to >100 ng/mL.9
Data Analysis
Results are expressed as mean±SEM. Sympathetic nerve firing
rate was corrected for background noise by subtracting postmortem
measurements from the measurement obtained at each time point when
alive. Values from the 3 separate baseline measurements did not differ
significantly for any parameter and were therefore averaged
for each animal. Because there is significant interindividual variation
in baseline SNA, these data are also expressed as percentage change
from baseline. Differences between active treated and control rats were
assessed by use of a repeated-measures ANOVA, with statistical testing
by Scheffé's F test. Statistical analysis was
performed by use of StatView software for the Macintosh (version 4,
Abacus Concepts Inc). We considered P<0.05 to be
statistically significant.
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Results |
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Sympathetic Effects of Melanocortin Receptor Stimulation
Third cerebral ventricle administration of the MC3/4-R agonist MT-II produced a slow and dose-dependent increase in SNA to BAT, with a 252±53% increase at the highest dose (P=0.0001 versus vehicle, ANOVA; the Table
and Figures 1 and 2).
MT-II also increased lumbar SNA (P=0.001, ANOVA) and, to a
lesser degree, renal SNA (P=0.04, ANOVA; Table and
Figure 1). Sympathoexcitation to MT-II was completely blocked by
administration of the MC3/4-R antagonist SHU9119
(P=0.002 versus MT-II, ANOVA; Table and Figure 2), which had no effects when given alone. Administration of
MT-II or SHU9119 did not significantly alter arterial
pressure, heart rate, or blood glucose compared with vehicle
(Table).
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) on BAT
sympathoactivation induced by
intracerebroventricular administration
of MC3/4-R agonist MT-II (
). SHU9119 completely blocked increase in
BAT SNA produced by MT-II (P<0.002 vs MT-II alone,
ANOVA). B, Effect of
intracerebroventricular administration
of MC3/4-R antagonist SHU9119 (
Role of Melanocortin Receptor in Sympathoexcitation to
Leptin
Intravenous administration of leptin slowly
increased SNA to BAT (455± 114%; P=0.001, ANOVA) and
kidney (50± 21%; P=0.014, ANOVA). The
sympathoexcitatory effect of leptin on BAT SNA
was not affected by pretreatment with the MC3/4-R
antagonist SHU9119 (P=0.71, ANOVA; Figure 3). In contrast, renal sympathoexcitation
to leptin was abolished by pretreatment with SHU9119
(P=0.007, ANOVA; Figure 3). Administration of leptin
or SHU9119 did not alter arterial pressure, heart rate, or
blood glucose compared with vehicle (Table
).
|
). SHU9119
had no effect on increase in BAT SNA produced by leptin
(P=0.71 vs leptin alone, ANOVA). B, Effect of
intracerebroventricular administration
of MC3/4-R antagonist SHU9119 (30 pmol; |
Discussion |
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The data from these studies demonstrate that stimulation of hypothalamic melanocortin receptors by third cerebral ventricular injection of an MC3/4-R agonist produces progressive sympathoexcitation to BAT, skeletal muscle, and kidney. This is not a nonspecific effect of the agonist because sympathoactivation can be completely blocked by coadministration of the MC3/4-R antagonist SHU9119. Melanocortins do not appear to be involved in leptin-induced thermogenic sympathoactivation because this effect of leptin was not affected by coadministration of the melanocortin receptor antagonist. In contrast, SHU9119 did block renal sympathoactivation to leptin. These results suggest that sympathoactivation caused by leptin has heterogeneous neural mechanisms, which only partly involve the melanocortin system.
The melanocortin system is now understood to comprise a series of peptides derived from POMC, including adrenocorticotrophin, endorphins, and MSH, that bind to at least 5 specific receptors. The agouti yellow obesity syndrome in mice is due to a gene mutation that produces overexpression of agouti protein, an endogenous melanocortin receptor antagonist.14 Agouti protein produces obesity through antagonism of MC4-R situated in the hypothalamic arcuate and paraventricular nuclei.14 19 Pharmacological stimulation of hypothalamic MC4-R suppresses feeding in hyperphagic lean and obese rats, whereas blockade of MC4-R by SHU9119 stimulates feeding.6 Furthermore, targeted disruption of the MC4-R receptor in mice reproduces the characteristic features of the agouti obesity syndrome.5
Leptin decreases weight and adipose tissue mass through inhibition of food intake and stimulation of thermogenic metabolism.20 21 22 The increase in energy expenditure is probably mediated by sympathetically mediated thermogenesis because we and others have shown that leptin increases sympathetic outflow to thermogenic and nonthermogenic tissue.9 23 Melanocortin receptor agonists also decrease appetite and body mass6 24 25 and increase body temperature.26 27 The mechanisms underlying melanocortin-induced thermogenesis had not been explored before this study. Our finding that activation of the melanocortin system increases sympathetic nerve traffic to BAT, hind limb, and kidney suggests that melanocortins, like leptin, can stimulate sympathetically mediated thermogenesis.
The role of melanocortins in the metabolic and autonomic effects of leptin is controversial. Some lines of evidence suggest an interaction between leptin and melanocortins. First, leptin receptor mRNA is colocalized with POMC mRNA in arcuate-nucleus neurons.28 Second, leptin-deficient obese mice have reduced hypothalamic POMC mRNA, which can be normalized by leptin replacement.29 30 Third, leptin-induced anorexia, expression of BAT uncoupling protein (UCP-1), and weight loss can be prevented by pretreatment with SHU9119.31 32 Fourth, obese agouti mice are resistant to the weight-reducing effects of centrally administered leptin.15 On the other hand, double-mutant leptin-deficient obese mice that also possess the agouti mutation are more obese than mice with leptin deficiency alone.16 This would suggest that the melanocortin and leptin pathways have independent effects on body weight.16 In addition, leptin resistance in agouti mice appears to be secondary to compensatory hyperleptinemia because this resistance disappears in agouti mice that have both leptin genes deleted.16 No studies have examined the contribution of melanocortins to sympathoactivation caused by leptin, although there is 1 report that stimulation of BAT UCP-1 expression by intracerebroventricular leptin can be blocked by SHU9119.32 We have shown here that thermogenic sympathoactivation to leptin is not altered by pretreatment with the MC4-R antagonist SHU9119. Our data suggest that the melanocortin system does not play a role in leptin-induced sympathetically mediated thermogenesis. Given that NPY can modulate thermogenic sympathoactivation8 and that obesity caused by leptin deficiency can be ameliorated by deletion of the NPY gene,3 leptin-induced BAT sympathoactivation may be modulated by hypothalamic NPY. In contrast, SHU9119 did block renal sympathoactivation to leptin, supporting a role for melanocortins in the effects of leptin on SNA to kidney. The discrepant effects of SHU9119 on BAT and renal SNA indicate divergent central pathways underlying leptin-induced sympathoactivation to BAT and kidney.
It is of interest that melanocortin receptor stimulation and leptin infusion did not alter arterial pressure or heart rate despite marked increases in renal, hind-limb, and adrenal SNA. The reason may be that the rats were anesthetized or that the degree or duration of sympathoexcitation was insufficient to acutely increase pressure. However, it is possible that the sympathoactivation represents increases mainly in nerve fibers that subserve thermogenesis through activation of uncoupling proteins, without altering vascular tone. Alternatively, the lack of a pressor effect may indicate other actions that oppose sympathetically mediated actions on the heart and blood vessels. These could include activation of vagal tone or neurally mediated vasodilator mechanisms. Given the absence of a change in heart rate and arterial pressure, is the sympathoactivation likely to be of physiological significance? In addition to its important role in short-term cardiovascular regulation, the sympathetic nervous system also stimulates renal tubular sodium excretion and vascular smooth muscle growth.33 34 Thus, increases in SNA may be functionally and pathophysiologically relevant in the absence of short-term changes in arterial pressure.
Several potential limitations of this study need to be addressed. First, rats were anesthetized, and it could be argued that different results would have been obtained in conscious rats. However, we have previously demonstrated that the anesthesia regimen used here does not alter efferent renal and lumbar sympathetic responses to baroreflex stimuli or hemorrhage.35 Second, it is possible that the lack of effect of SHU9119 on leptin-induced BAT sympathoactivation was due to an inadequate dose of the MC3/4-R antagonist. However, this dose was sufficient to block the effect of an MC3/4-R agonist on sympathetic nerve traffic and to block the effect of leptin on renal sympathetic nerve traffic. Third, our study does not delineate the relative contributions of increased thermogenesis and decreased appetite in the weight-reducing effect of melanocortin system. Studies in pair-fed animals are required to do this. Fourth, our study does not address whether the melanocortin system plays a physiological role in regulation of sympathetic nerve traffic. Proof of such a role would require examination of the effects of MC4-R blockade on sympathetic responses to stimuli such as hypotension, feeding, or hypothermia. Finally, our conclusions on the role of the melanocortin system in rats cannot be directly extrapolated to humans.
In conclusion, we have demonstrated that stimulation of central nervous system melanocortin receptors increases sympathetic nerve traffic to thermogenic and nonthermogenic tissues. This action may promote weight loss by increasing thermogenic metabolism in addition to the well-known inhibitory effects of melanocortins on appetite. It is also possible that the effects of MC3/4-R stimulation on SNA to nonthermogenic tissues may have deleterious long-term cardiovascular effects. We have also shown that leptin-induced BAT sympathoactivation is not dependent on the melanocortin system. However, the effects of leptin on renal SNA are prevented by MC3/4-R blockade. These data suggest that sympathoactivation caused by leptin has heterogeneous neural mechanisms, which only partly involve the melanocortin system.
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Acknowledgments |
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Research was supported by grants HL-14388, HL-44546 and HL-43514 from the National Heart, Lung, and Blood Institute; by grant DK-25295 from the National Institute of Diabetes, Digestive, and Kidney Diseases; by grant NS-38846 from the National Institute of Neurological Disorders and Stroke; and by funds from the Department of Veterans Affairs and the Juvenile Diabetes Foundation. Dr Haynes is the recipient of a PhRMAF Faculty Development Award.
Received September 18, 1998; first decision October 23, 1998; accepted November 5, 1998.
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C. M. Patterson, A. A. Dunn-Meynell, and B. E. Levin Three weeks of early-onset exercise prolongs obesity resistance in DIO rats after exercise cessation Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R290 - R301. [Abstract] [Full Text] [PDF]
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M. N. Brito, N. A. Brito, D. J. Baro, C. K. Song, and T. J. Bartness Differential Activation of the Sympathetic Innervation of Adipose Tissues by Melanocortin Receptor Stimulation Endocrinology, November 1, 2007; 148(11): 5339 - 5347. [Abstract] [Full Text] [PDF]
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 M. Lee, A. Kim, S. C. Chua Jr., S. Obici, and S. L. Wardlaw Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E121 - E131. [Abstract] [Full Text] [PDF]
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R. B. S. Harris, T. D. Mitchell, E. W. Kelso, and W. P. Flatt Changes in environmental temperature influence leptin responsiveness in low- and high-fat-fed mice Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R106 - R115. [Abstract] [Full Text] [PDF]
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J. N. Gorski, A. A. Dunn-Meynell, and B. E. Levin Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1782 - R1791. [Abstract] [Full Text] [PDF]
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M. S. Landa, S. I. Garcia, M. L. Schuman, A. Burgueno, A. L. Alvarez, F. E. Saravia, C. Gemma, and C. J. Pirola Knocking down the diencephalic thyrotropin-releasing hormone precursor gene normalizes obesity-induced hypertension in the rat Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1388 - E1394. [Abstract] [Full Text] [PDF]
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 H. Shimizu, K. Inoue, and M. Mori The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure J. Endocrinol., April 1, 2007; 193(1): 1 - 9. [Abstract] [Full Text] [PDF]
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A. Voss-Andreae, J. G. Murphy, K. L. J. Ellacott, R. C. Stuart, E. A. Nillni, R. D. Cone, and W. Fan Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue Endocrinology, April 1, 2007; 148(4): 1550 - 1560. [Abstract] [Full Text] [PDF]
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S. D. Stocker, R. Meador, and J. M. Adams Neurons of the Rostral Ventrolateral Medulla Contribute to Obesity-Induced Hypertension in Rats Hypertension, March 1, 2007; 49(3): 640 - 646. [Abstract] [Full Text] [PDF]
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K. Diepvens, K. R. Westerterp, and M. S. Westerterp-Plantenga Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R77 - R85. [Abstract] [Full Text] [PDF]
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 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]
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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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 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]
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M. Perello, R. C. Stuart, and E. A. Nillni The Role of Intracerebroventricular Administration of Leptin in the Stimulation of Prothyrotropin Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus Endocrinology, July 1, 2006; 147(7): 3296 - 3306. [Abstract] [Full Text] [PDF]
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L. S. Tallam, A. A. da Silva, and J. E. Hall Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin Hypertension, July 1, 2006; 48(1): 58 - 64. [Abstract] [Full Text] [PDF]
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A. A. da Silva, J. J. Kuo, L. S. Tallam, J. Liu, and J. E. Hall Does Obesity Induce Resistance to the Long-Term Cardiovascular and Metabolic Actions of Melanocortin 3/4 Receptor Activation? Hypertension, February 1, 2006; 47(2): 259 - 264. [Abstract] [Full Text] [PDF]
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C. K. Song, R. M. Jackson, R. B. S. Harris, D. Richard, and T. J. Bartness Melanocortin-4 receptor mRNA is expressed in sympathetic nervous system outflow neurons to white adipose tissue Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1467 - R1476. [Abstract] [Full Text] [PDF]
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J. L. Trevaskis and A. A. Butler Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake Endocrinology, October 1, 2005; 146(10): 4257 - 4265. [Abstract] [Full Text] [PDF]
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 Y. Zhang, G. E Kilroy, T. M. Henagan, V. Prpic-Uhing, W. G. Richards, A. W. Bannon, R. L. Mynatt, and T. W. Gettys Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin FASEB J, September 1, 2005; 19(11): 1482 - 1491. [Abstract] [Full Text] [PDF]
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 W. G Haynes Role of leptin in obesity-related hypertension Exp Physiol, September 1, 2005; 90(5): 683 - 688. [Abstract] [Full Text] [PDF]
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 N Hoggard, D V Rayner, S L Johnston, and J R Speakman Peripherally administered [Nle4,D-Phe7]-{alpha}-melanocyte stimulating hormone increases resting metabolic rate, while peripheral agouti-related protein has no effect, in wild type C57BL/6 and ob/ob mice J. Mol. Endocrinol., December 1, 2004; 33(3): 693 - 703. [Abstract] [Full Text] [PDF]
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L. S. Tallam, J. J. Kuo, A. A. da Silva, and J. E. Hall Cardiovascular, Renal, and Metabolic Responses to Chronic Central Administration of Agouti-Related Peptide Hypertension, December 1, 2004; 44(6): 853 - 858. [Abstract] [Full Text] [PDF]
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 R. Gutierrez-Juarez, S. Obici, and L. Rossetti Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes J. Biol. Chem., November 26, 2004; 279(48): 49704 - 49715. [Abstract] [Full Text] [PDF]
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E. Savontaus, T. L. Breen, A. Kim, L. M. Yang, S. C. Chua Jr., and S. L. Wardlaw Metabolic Effects of Transgenic Melanocyte-Stimulating Hormone Overexpression in Lean and Obese Mice Endocrinology, August 1, 2004; 145(8): 3881 - 3891. [Abstract] [Full Text] [PDF]
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G. S. Gopalakrishnan, D. S. Gardner, S. M. Rhind, M. T. Rae, C. E. Kyle, A. N. Brooks, R. M. Walker, M. M. Ramsay, D. H. Keisler, T. Stephenson, et al. Programming of adult cardiovascular function after early maternal undernutrition in sheep Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R12 - R20. [Abstract] [Full Text] [PDF]
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 P. Chen, S. M. Williams, K. L. Grove, and M. S. Smith Melanocortin 4 Receptor-Mediated Hyperphagia and Activation of Neuropeptide Y Expression in the Dorsomedial Hypothalamus during Lactation J. Neurosci., June 2, 2004; 24(22): 5091 - 5100. [Abstract] [Full Text] [PDF]
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A. A. da Silva, J. J. Kuo, and J. E. Hall Role of Hypothalamic Melanocortin 3/4-Receptors in Mediating Chronic Cardiovascular, Renal, and Metabolic Actions of Leptin Hypertension, June 1, 2004; 43(6): 1312 - 1317. [Abstract] [Full Text] [PDF]
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Y. Lin, K. Matsumura, M. Fukuhara, S. Kagiyama, K. Fujii, and M. Iida Ghrelin Acts at the Nucleus of the Solitary Tract to Decrease Arterial Pressure in Rats Hypertension, May 1, 2004; 43(5): 977 - 982. [Abstract] [Full Text] [PDF]
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 S. T. Weiss and S. Shore Obesity and Asthma: Directions for Research Am. J. Respir. Crit. Care Med., April 15, 2004; 169(8): 963 - 968. [Full Text] [PDF]
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 S. F. Morrison Central Pathways Controlling Brown Adipose Tissue Thermogenesis Physiology, April 1, 2004; 19(2): 67 - 74. [Abstract] [Full Text] [PDF]
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B. E. Levin and A. A. Dunn-Meynell Chronic exercise lowers the defended body weight gain and adiposity in diet-induced obese rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R771 - R778. [Abstract] [Full Text] [PDF]
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 T. Yasuda, T. Masaki, T. Kakuma, and H. Yoshimatsu Hypothalamic Melanocortin System Regulates Sympathetic Nerve Activity in Brown Adipose Tissue Experimental Biology and Medicine, March 1, 2004; 229(3): 235 - 239. [Abstract] [Full Text] [PDF]
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D. R. Seals and C. Bell Chronic Sympathetic Activation: Consequence and Cause of Age-Associated Obesity? Diabetes, February 1, 2004; 53(2): 276 - 284. [Abstract] [Full Text]
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Z.-H. Zhang and R. B. Felder Melanocortin receptors mediate the excitatory effects of blood-borne murine leptin on hypothalamic paraventricular neurons in rat Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2004; 286(2): R303 - R310. [Abstract] [Full Text] [PDF]
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J. J. Kuo, A. A. da Silva, L. S. Tallam, and J. E. Hall Role of Adrenergic Activity in Pressor Responses to Chronic Melanocortin Receptor Activation Hypertension, February 1, 2004; 43(2): 370 - 375. [Abstract] [Full Text] [PDF]
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 A. Aneja, F. El-Atat, S. I. McFarlane, and J. R. Sowers Hypertension and Obesity Recent Prog. Horm. Res., January 1, 2004; 59(1): 169 - 205. [Abstract] [Full Text]
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K. Rahmouni and W. G. Haynes Leptin and the Cardiovascular System Recent Prog. Horm. Res., January 1, 2004; 59(1): 225 - 244. [Abstract] [Full Text]
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F. F. Chehab, J. Qiu, and S. Ogus The Use of Animal Models to Dissect the Biology of Leptin Recent Prog. Horm. Res., January 1, 2004; 59(1): 245 - 266. [Abstract] [Full Text]
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C. Bjorbaek and B. B. Kahn Leptin Signaling in the Central Nervous System and the Periphery Recent Prog. Horm. Res., January 1, 2004; 59(1): 305 - 331. [Abstract] [Full Text]
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C. B. Lawrence, Y.-L. Liu, M. J. Stock, and S. M. Luckman Anorectic actions of prolactin-releasing peptide are mediated by corticotropin-releasing hormone receptors Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2004; 286(1): R101 - R107. [Abstract] [Full Text]
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K. R. Hansen, S. M. Krasnow, M. A. Nolan, G. S. Fraley, J. W. Baumgartner, D. K. Clifton, and R. A. Steiner Activation of the Sympathetic Nervous System by Galanin-Like Peptide--A Possible Link between Leptin and Metabolism Endocrinology, November 1, 2003; 144(11): 4709 - 4717. [Abstract] [Full Text] [PDF]
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D. L. Williams, R. R. Bowers, T. J. Bartness, J. M. Kaplan, and H. J. Grill Brainstem Melanocortin 3/4 Receptor Stimulation Increases Uncoupling Protein Gene Expression in Brown Fat Endocrinology, November 1, 2003; 144(11): 4692 - 4697. [Abstract] [Full Text] [PDF]
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A. J. Marsh, M. A.P. Fontes, S. Killinger, D. B. Pawlak, J. W. Polson, and R. A.L. Dampney Cardiovascular Responses Evoked by Leptin Acting on Neurons in the Ventromedial and Dorsomedial Hypothalamus Hypertension, October 1, 2003; 42(4): 488 - 493. [Abstract] [Full Text] [PDF]
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K. Rahmouni, W. G. Haynes, D. A. Morgan, and A. L. Mark Role of Melanocortin-4 Receptors in Mediating Renal Sympathoactivation to Leptin and Insulin J. Neurosci., July 9, 2003; 23(14): 5998 - 6004. [Abstract] [Full Text] [PDF]
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V. Prpic, P. M. Watson, I. C. Frampton, M. A. Sabol, G. E. Jezek, and T. W. Gettys Differential Mechanisms and Development of Leptin Resistance in A/J Versus C57BL/6J Mice during Diet-Induced Obesity Endocrinology, April 1, 2003; 144(4): 1155 - 1163. [Abstract] [Full Text] [PDF]
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J. J. Kuo, O. B. Jones, and J. E. Hall Chronic cardiovascular and renal actions of leptin during hyperinsulinemia Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R1037 - R1042. [Abstract] [Full Text] [PDF]
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T. Shirasaka, M. Takasaki, and H. Kannan Cardiovascular effects of leptin and orexins Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R639 - R651. [Abstract] [Full Text] [PDF]
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J. E. Hall The Kidney, Hypertension, and Obesity Hypertension, March 1, 2003; 41(3): 625 - 633. [Abstract] [Full Text] [PDF]
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J. J. Kuo, A. A. Silva, and J. E. Hall Hypothalamic Melanocortin Receptors and Chronic Regulation of Arterial Pressure and Renal Function Hypertension, March 1, 2003; 41(3): 768 - 774. [Abstract] [Full Text] [PDF]
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K. Matsumura, T. Tsuchihashi, K. Fujii, I. Abe, and M. Iida Central Ghrelin Modulates Sympathetic Activity in Conscious Rabbits Hypertension, November 1, 2002; 40(5): 694 - 699. [Abstract] [Full Text] [PDF]
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P. Cettour-Rose and F. Rohner-Jeanrenaud The Leptin-Like Effects of 3-d Peripheral Administration of a Melanocortin Agonist Are More Marked in Genetically Obese Zucker (fa/fa) than in Lean Rats Endocrinology, June 1, 2002; 143(6): 2277 - 2283. [Abstract] [Full Text] [PDF]
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M. L.G. Correia, W. G. Haynes, K. Rahmouni, D. A. Morgan, W. I. Sivitz, and A. L. Mark The Concept of Selective Leptin Resistance: Evidence From Agouti Yellow Obese Mice Diabetes, February 1, 2002; 51(2): 439 - 442. [Abstract] [Full Text] [PDF]
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M. L.G. Correia, D. A. Morgan, J. L. Mitchell, W. I. Sivitz, A. L. Mark, and W. G. Haynes Role of Corticotrophin-Releasing Factor in Effects of Leptin on Sympathetic Nerve Activity and Arterial Pressure Hypertension, September 1, 2001; 38(3): 384 - 388. [Abstract] [Full Text] [PDF]
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J. J. Hwa, L. Ghibaudi, J. Gao, and E. M. Parker Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R444 - R451. [Abstract] [Full Text] [PDF]
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T. Adage, A. J. W. Scheurink, S. F. de Boer, K. de Vries, J. P. Konsman, F. Kuipers, R. A. H. Adan, D. G. Baskin, M. W. Schwartz, and G. van Dijk Hypothalamic, Metabolic, and Behavioral Responses to Pharmacological Inhibition of CNS Melanocortin Signaling in Rats J. Neurosci., May 15, 2001; 21(10): 3639 - 3645. [Abstract] [Full Text] [PDF]
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C. J. Small, M. S. Kim, S. A. Stanley, J. R.D. Mitchell, K. Murphy, D. G.A. Morgan, M. A. Ghatei, and S. R. Bloom Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals Diabetes, February 1, 2001; 50(2): 248 - 254. [Abstract] [Full Text]
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J. M. Overton, T. D. Williams, J. B. Chambers, and M. E. Rashotte Central Leptin Infusion Attenuates the Cardiovascular and Metabolic Effects of Fasting in Rats Hypertension, February 1, 2001; 37(2): 663 - 669. [Abstract] [Full Text] [PDF]
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W. Fan, D. M. Dinulescu, A. A. Butler, J. Zhou, D. L. Marks, and R. D. Cone The Central Melanocortin System Can Directly Regulate Serum Insulin Levels Endocrinology, September 1, 2000; 141(9): 3072 - 3079. [Abstract] [Full Text] [PDF]
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 K. AMANN, L. C. RUMP, A. SIMONAVICIENE, V. OBERHAUSER, S. WESSELS, S. R. ORTH, M.-L. GROSS, A. KOCH, G. W. BIELENBERG, J. P. VAN KATS, et al. Effects of Low Dose Sympathetic Inhibition on Glomerulosclerosis and Albuminuria in Subtotally Nephrectomized Rats J. Am. Soc. Nephrol., August 1, 2000; 11(8): 1469 - 1478. [Abstract] [Full Text]
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K. Matsumura, I. Abe, T. Tsuchihashi, and M. Fujishima Central effects of leptin on cardiovascular and neurohormonal responses in conscious rabbits Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1314 - R1320. [Abstract] [Full Text] [PDF]
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D. L. Williams, J. M. Kaplan, and H. J. Grill The Role of the Dorsal Vagal Complex and the Vagus Nerve in Feeding Effects of Melanocortin-3/4 Receptor Stimulation Endocrinology, April 1, 2000; 141(4): 1332 - 1337. [Abstract] [Full Text] [PDF]
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