This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Haynes, W. G. Articles by Mark, A. L. Search for Related Content PubMed PubMed Citation Articles by Haynes, W. G. Articles by Mark, A. L. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

(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

William G. Haynes; Donald A. Morgan; Ali Djalali; William I. Sivitz; Allyn L. Mark

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

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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}

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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 (K_i 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 (K_i 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.

	Results

Top Abstract Introduction Methods Results Discussion References

 
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).

View this table: [in this window] [in a new window]   Table 1. Hemodynamic, SNA, and Blood Glucose Data Obtained From Sprague-Dawley Rats at Baseline and 6 Hours After Administration of Study Agents

View larger version (13K): [in this window] [in a new window]   Figure 1. A, Effect of various intracerebroventricular doses of melanocortin receptor agonist MT-II on SNA to BAT(*P<0.05 vs vehicle, ANOVA). B, Effect of MT-II (600 pmol ICV) and vehicle on SNA to kidney, BAT, and hind limb. (*P<0.05 vs vehicle, ANOVA).

View larger version (24K): [in this window] [in a new window]   Figure 2. A, Effect of intracerebroventricular administration of MC3/4-R antagonist SHU9119 () 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 () on renal sympathoactivation induced by intracerebroventricular administration of MC3/4-R agonist MT-II (). SHU9119 completely blocked increase in BAT SNA produced by MT-II (P<0.02 vs MT-II alone, ANOVA).

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).

View larger version (22K): [in this window] [in a new window]   Figure 3. A, Effect of intracerebroventricular administration of MC3/4-R antagonist SHU9119 (30 pmol; ) on BAT sympathoactivation induced by leptin (1000 µg/kg IV; ). 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; ) on renal sympathoactivation induced by leptin (1000 µg/kg IV; ). SHU9119 completely blocked increase in renal SNA produced by leptin (P < 0.001 vs leptin alone, ANOVA).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
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 mass^{6 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.

	Acknowledgments

 
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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432.[Medline] [Order article via Infotrieve]
2. Stephens TW, Basinski M, Bristow PK, Bue-Vallesky JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hslung HM, Kriauciunas A, MacKellar W, Rosteck PR, Schoner B, Smith D, Tinsley FC, Zhang X-Y, Heiman M. The role of neuropeptide Y in the anti-obesity action of the obese gene product. Nature. 1995;377:530–532.[Medline] [Order article via Infotrieve]
3. Erickson JC, Hollopeter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by loss of neuropeptide Y. Science. 1996;274:1704–1708.[Abstract/Free Full Text]
4. Schwartz M, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 1996;98:1101–1106.[Medline] [Order article via Infotrieve]
5. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131–141.[Medline] [Order article via Infotrieve]
6. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997;385:165–168.[Medline] [Order article via Infotrieve]
7. Egawa M, Yoshimatsu H, Bray GA. Preoptic area injection of corticotrophin-releasing hormone stimulates sympathetic activity. Am J Physiol. 1990;259:R799–R806.[Abstract/Free Full Text]
8. Egawa M, Yoshimatsu H, Bray GA. Neuropeptide Y suppresses sympathetic activity to interscapular brown adipose tissue in rats. Am J Physiol. 1991;260:R329–R334.
9. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100:270–278.[Medline] [Order article via Infotrieve]
10. Chagnon YC, Chen WJ, Perusse L, Chagnon M, Nadeau A, Wilkison WO, Bouchard C. Linkage and association between the melanocortin receptors 4 and 5 genes and obesity related phenotypes in the Quebec Family Study. Mol Med. 1997;3:663–673.[Medline] [Order article via Infotrieve]
11. Comuzzie AG, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, Stern MP, MacCluer JW, Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet. 1997;15:273–276.[Medline] [Order article via Infotrieve]
12. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency, and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155–157.[Medline] [Order article via Infotrieve]
13. Schiàth HB, Muceniece R, Larsson M, Mutulis F, Szardenings M, Prusis P, Lindberg G, Wilkberg JES. Selectivity of cyclic [D-Phe⁷] and [d -Nal⁷] substituted MSH analogues for the melanocortin receptors. Peptides. 1997;18:1009–1013.[Medline] [Order article via Infotrieve]
14. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkinson WO, Cone RD. Agouti protein is an antagonist of the melanocyte-stimulating hormone receptor. Nature. 1994;371:799–802.[Medline] [Order article via Infotrieve]
15. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A. 1997;94:8878–8883.[Abstract/Free Full Text]
16. Boston BA. Blaydon KM. Varnerin J. Cone RD. Independent and additive effects of central POMC and leptin pathways on murine obesity. Science. 1997;278:1641–1644.[Abstract/Free Full Text]
17. Muntzel MS, Morgan DA, Mark AL, Johnson AK. Intracerebroventricular administration of insulin produces nonuniform regional increases in sympathetic nerve activity. Am J Physiol. 1994;267:R1350–R1355.[Abstract/Free Full Text]
18. Morgan DA, Balon TW, Ginsberg BH, Mark AL. Nonuniform regional sympathetic nerve responses to hyperinsulinemia in rats. Am J Physiol. 1993;264:R423–R427.[Abstract/Free Full Text]
19. Low MJ, Simerly RB, Cone RD. Receptors for the melanocortin peptides in the central nervous system. Curr Opin Endocrinol Diabetes. 1994;1:79–88.
20. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–549.[Abstract/Free Full Text]
21. Halaas JL, Gajiwalla KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight reducing effects of the plasma protein encoded by the obese gene. Science. 1995;269:543–546.[Abstract/Free Full Text]
22. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269:540–543.[Abstract/Free Full Text]
23. Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk BA, Surwit RS. Role of leptin in fat regulation. Nature. 1996;380:677–682.[Medline] [Order article via Infotrieve]
24. Thiele TE, van Dijk G, Yagaloff KA, Fisher SL, Schwartz M, Burn P, Seeley RJ. Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am J Physiol. 1998;274:R248–R54.
25. Kask A, Rago L, Mutulis F, Pahkla R, Wikberg JES, Schiàth HB. Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats. Biochem Biophys Res Commun. 1998;245:90–93.[Medline] [Order article via Infotrieve]
26. Feng JD, Dao T, Lipton JM. Effects of preoptic microinjections of alpha-MSH on fever and normal temperature control in rabbits. Brain Res. 1987;18:473–477.
27. Zemel MB, Moore JW, Moustaid N, Kim JH, Nichols JS, Blanchard SG, Parks DJ, Harris C, Lee FW, Grizzle M, James M, Wilkison WO. Effects of a potent melanocortin agonist on the diabetic/obese phenotype in yellow mice. Int J Obes. 1998;22:678–683.
28. Cheung C, Thornton J, Kuijper J, Weigle D, Clifton D, Steiner R. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 1997;138:4489–4493.[Abstract/Free Full Text]
29. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG. Leptin increases hypothalamic proopiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes. 1997;46:2119–2123.[Abstract]
30. Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology. 1997;138:5063–5066.[Abstract/Free Full Text]
31. Seeley RJ, Yagaloff KA, Fisher SL, Burn P, Thiele TE, van Dijk G, Baskin DG, Schwartz MW. Melanocortin receptors in leptin effects. Nature. 1997;390:349. Letter.[Medline] [Order article via Infotrieve]
32. Satoh N, Ogawa Y, Katsura G, Numata Y, Masuzaki H, Yoshimasa Y, Nakao K. Satiety effect and sympathetic activation of leptin are mediated by melanocortin system. Neurosci Lett. 1998;249:107–110.[Medline] [Order article via Infotrieve]
33. Hart MN., Heistad DD, Brody MJ. Effect of chronic hypertension and sympathetic denervation on wall/lumen ratio of cerebral vessels. Hypertension. 1980;2:419–423.[Abstract/Free Full Text]
34. DiBona GF. Sympathetic nervous system influences on the kidney: role of hypertension. Am J Hypertens. 1989;2:119S–124S.[Medline] [Order article via Infotrieve]
35. Morgan DA, Thorén P, Staudt SM, Mark AL. Differential effects of anesthesia on heart rate (HR), renal (RSNA), and lumbar sympathetic nerve activity (LSNA) in the rat. FASEB J. 1988;2:A1690. Abstract.

This article has been cited by other articles:

				J. Krakoff, L. Ma, S. Kobes, W. C. Knowler, R. L. Hanson, C. Bogardus, and L. J. Baier Lower Metabolic Rate in Individuals Heterozygous for Either a Frameshift or a Functional Missense MC4R Variant Diabetes, December 1, 2008; 57(12): 3267 - 3272. [Abstract] [Full Text] [PDF]

				K. P. Skibicka and H. J. Grill Energetic Responses Are Triggered by Caudal Brainstem Melanocortin Receptor Stimulation and Mediated by Local Sympathetic Effector Circuits Endocrinology, July 1, 2008; 149(7): 3605 - 3616. [Abstract] [Full Text] [PDF]

				A. A. da Silva, J. M. do Carmo, B. Kanyicska, J. Dubinion, E. Brandon, and J. E. Hall Endogenous Melanocortin System Activity Contributes to the Elevated Arterial Pressure in Spontaneously Hypertensive Rats Hypertension, April 1, 2008; 51(4): 884 - 890. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				W. G Haynes Role of leptin in obesity-related hypertension Exp Physiol, September 1, 2005; 90(5): 683 - 688. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

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]