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The Journal of Neuroscience, July 9, 2003, 23(14):5998-6004
Previous Article | Next Article
Role of Melanocortin-4 Receptors in Mediating Renal Sympathoactivation to Leptin and Insulin
Kamal Rahmouni, William G. Haynes, Donald A. Morgan, andAllyn L. Mark Hypertension Genetics Specialized Center of Research, and Department of Internal Medicine, University of Iowa and the Veterans Administration Medical Center, Iowa City, Iowa 52242
Abstract
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Abstract
Introduction
Central melanocortin signaling plays an important role in regulation of energy homeostasis by leptin and insulin. We investigated the interaction between leptin, insulin, and melanocortin-4 receptors (MC-4Rs) in the control of renal sympathetic nerve activity (RSNA) in mice. We compared the effects of intracerebroventricular (ICV) administration of leptin, insulin, MC-3/4R agonist (MTII), and corticotrophin-releasing factor (CRF) on RSNA in leptin receptor-deficient (db/db) mice, MC-4R knock-out mice, and their wild-type controls. ICV administration of leptin and MTII caused a significant and dose-dependent increase in RSNA in control mice. As expected, leptin had no significant effect on RSNA in the db/db mice. Interestingly, db/db mice exhibited markedly attenuated RSNA responses to ICV administration of MTII. However, the increase in RSNA induced by insulin and CRF was comparable between db/db and control mice. In the heterozygous and homozygous MC-4R knock-out mice, the RSNA response to MTII was attenuated and abolished, respectively. The RSNA response to ICV leptin and insulin was also attenuated and abolished in the heterozygous and homozygous MC-4R knock-out mice, respectively. In contrast, CRF induced a similar increase in RSNA in the MC-4R knock-out and wild-type mice. Our data demonstrate that in the absence of leptin receptors, the sympathoexcitatory effects of melanocortin system stimulation are attenuated. In addition, the renal sympathoexcitatory responses to leptin and insulin are dependent on the MC-4R, demonstrating an important role for the MC-4R in the regulation of renal sympathetic nerve outflow by leptin and insulin.
Key words: obesity; melanocortin system; leptin; insulin; sympathetic nerve activity; hypothalamus
Introduction
Leptin and insulin act in the CNS as afferent signals, to regulate food intake and energy expenditure (Schwartz et al., 2000). The action of these two hormones in the CNS is also known to modulate several other functions, including sympathetic nerve activity (Muntzel et al., 1995
Receptors for leptin and insulin are expressed in several sites in the brain including the arcuate nucleus of the hypothalamus (Schwartz et al., 2000
The physiological role of brain insulin receptors in the regulation of energy balance has been demonstrated by neuron-specific deletion of this receptor throughout the CNS, which results in a marked increase in fat mass (Bruning et al., 2000
Several observations suggest that the melanocortin system is an essential mediator for leptin and insulin action in the CNS (Schwartz et al., 2000
-melanocyte-stimulating hormone (
The implication of the MC-4R in the control of sympathetic nerve activity is more controversial, however. In rat, we have shown previously that the effects of leptin on renal sympathetic nerve activity (RSNA) are mediated by the melanocortin receptors because intracerebroventricular (ICV) administration of the MC-3/4R antagonist SHU9119 blocks the sympathoexcitatory effects of leptin to the kidney but not to brown adipose tissue (Haynes et al., 1999
In the present study, we evaluated the interaction between leptin, insulin, and the MC-4R in the regulation of sympathetic nerve outflow to the kidney. First, to evaluate the consequences of absence of leptin receptors on the RSNA response to stimulation of MC-4R and insulin, we compared the effects of stimulation of the MC-4R on RSNA in leptin-deficient db/db mice and their control littermates. Second, we examined the role of the MC-4R in mediating the RSNA response to leptin and insulin. For this, we studied the effects of leptin and insulin on RSNA in the MC-4R knock-out mice and their wild-type littermates.
Materials and Methods
Animals. db/db mice (C57BL/KsJ-Lep db) and their littermate controls were purchased from the Jackson Laboratory (Bar Harbor, ME). Mice of mixed 129/Sv x C57BL/6J background heterozygous for the disrupted MC-4R allele were first obtained from Dr. Dennis Huszar (Millenium Pharmaceuticals, Cambridge, MA) and then bred to generate male and female MC4-R (-/-), MC-4R (+/-) and wild-type mice. Genotyping was performed by PCR as described (Marsh et al., 1999Cannula implantation. Adult mice were anesthetized by intraperitoneal injection of ketamine (91 mg/kg) and xylazine (9.1 mg/kg) and placed in a stereotactic device (Kopf Instruments). A sterile guide cannula 9 mm in length was implanted into the lateral brain ventricle (0.3 mm posterior and 1 mm lateral relative to bregma, and 3 mm below the surface of the skull). The cannula was then fixed in place using dental cement. After surgery, a 33 gauge wire plug was inserted into each cannula to prevent blockage. The position of the cannulas was verified at the end of the experiments by dye administration before animals were killed and by histological analysis.
Recording of hemodynamic and renal sympathetic nerve activity. After 5–7 d of postoperative recovery from ICV cannulation, mice were anesthetized using an intraperitoneal ketamine/xylazine mixture and a catheter inserted in the jugular vein for maintenance of anesthesia with
The nerve electrode was attached to a high-impedance probe (HIP-511, Grass Instruments). The nerve signal was amplified 10,000 times with a Grass P5 AC pre-amplifier, filtered at a 100 and 1000 Hz cutoff with a nerve traffic analysis system (model 706C, University of Iowa Bioengineering), and led to an oscilloscope (model 54501A, Hewlett-Packard) with a cursor that was positioned precisely above the background noise. The nerve traffic analyzer counted the action potentials that exceeded this threshold voltage. Both the counted action potentials and the renal neurogram were routed to a MacLab analog-to-digital converter (model 8S, AD Instruments) for permanent recording and data analysis on a Macintosh 9500 computer. To ensure that electrical noise was excluded in the assessment of sympathetic outflow, RSNA was corrected for postmortem background activity.
Experimental protocol. After surgery for RSNA recording was completed, animals were allowed to stabilize for 20 min. Baseline RSNA, mean arterial pressure (MAP), and heart rate (HR) were then collected on two occasions during a 10 min control period and averaged to obtain a single value for this control period. Each mouse received one ICV injection, over 1 min, of 2 µl of vehicle (0.9% NaCl) or one of the following agents: leptin (R & D Systems, Minneapolis, MN) at a dose of 0.5, 1, or 2 µg; MC-3/4R agonist MTII (Phoenix Pharmaceuticals) at a dose of 0.5 or 2 µg; 20 µU of insulin (Novo Nordisk Pharmaceuticals); or 5 µg of corticotrophin releasing factor (CRF) (Sigma Aldrich). Because it has been reported that the rise in RSNA induced by leptin may result from its peripheral action (Tanida et al., 2000
Plasma assay. Blood obtained from mice was immediately centrifuged at 5000 rpm for 5 min at room temperature. The collected plasma was frozen at -20°C. Plasma concentration of leptin and insulin were measured by radioimmunoassay using commercially available kits (both from Linco).
Data analysis. Because there is significant inter-individual variation in baseline RSNA, the data for RSNA are expressed as percentage change from baseline with 0% as baseline. The RSNA in the fourth hour represents the average of the four measurements obtained in the last hour of the experiment (maximal response). All results are expressed as mean ± SEM and analyzed using Student's t test, one-way ANOVA, or two-way ANOVA. When ANOVA reached significance, post hoc comparisons were made using Bonferroni test. p < 0.05 was considered to be statistically significant.
Results
Effects of leptin on RSNA in control and db/db mice
As shown in Table 1, the obese db/db mice had higher levels of MAP measured at baseline under anesthesia. Obese mice also had significantly higher baseline RSNA. The circulating levels of leptin and insulin were dramatically elevated in the db/db mice as compared with the control mice.
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Table 1. Body weight, hemodynamics, RSNA, and endocrine data obtained from db/db mice and their wild-type controls
To determine whether the sympathoexcitatory effects of leptin in mice were receptor mediated, we compared the RSNA response to leptin in control and leptin-deficient db/db mice. In control mice, ICV administration of different doses of leptin caused a significant and dose-dependent increase in RSNA (p = 0.001) (Fig. 1A), with a 297 ± 97% increase in the fourth hour after the 2 µg dose (p < 0.01 vs vehicle). Despite this robust increase in RSNA induced by ICV administration of 2 µg of leptin, arterial pressure did not change significantly (MAP was 80 ± 4 mmHg at baseline and 79 ± 8 mmHg in the fourth hour). In all groups, there was a tendency for HR to increase during the study (from 301 ± 18 bpm at baseline to 466 ± 70 bpm in the fourth hour after ICV administration of 2 µg of leptin), but the magnitude of the increase did not differ significantly between leptin and vehicle groups. As expected, the leptin receptor-deficient db/db mice exhibited markedly blunted RSNA responses to ICV administration of leptin (p = 0.81) (Fig. 1B).
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Figure 1. Effect of ICV administration of leptin on renal sympathetic nerve activity (RSNA) in control and db/db mice. A, Dose–response of RSNA to ICV administration of leptin in control mice. B, Absence of RSNA response to ICV administration of leptin in db/db mice. RSNA represents the percentage change in RSNA from baseline. Data represent means ± SEM; n = 7–9 mice for each group.
Because it has been shown that the renal sympathoexcitatory action of leptin could be caused by its systemic action (Tanida et al., 2000
Effects of insulin and CRF on RSNA in control and db/db mice
To determine whether absence of leptin receptors affects the sympathoexcitatory effects of stimulation of the melanocortin system, we compared the RSNA response to the MC-3/4R agonist MTII in control mice and db/db mice. As depicted in Figure 2A, ICV administration of MTII caused a significant (p = 0.0083) and dose-dependent increase in RSNA, with a 291 ± 68% (p < 0.01 vs vehicle) increase from baseline in the fourth hour at the highest dose. In db/db mice, MTII at a dose of 0.5 and 2 µg had no significant effect on RSNA (p = 0.83) (Fig. 2B). A 10-fold higher dose (20 µg) of MTII was required to induce a significant increase in RSNA (170 ± 40% in the fourth hour; p < 0.05) in db/db mice.
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Figure 2. Effect of ICV administration of MC-3/4R agonist (MTII) on renal sympathetic nerve activity (RSNA) in control mice and db/db mice. A, Dose–response of RSNA to ICV administration of MTII in control mice. B, Attenuated RSNA response to ICV administration of MTII in db/db mice.
To examine whether the RSNA response to other stimuli were attenuated in db/db mice, we assessed the effects of ICV administration of insulin (20 µU) and CRF (5 µg) in db/db mice and their littermate controls. As shown in Figure 3, both insulin and CRF caused a significant (p < 0.01) increase in RSNA in control and db/db mice with the same time course and magnitude.
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Figure 3. Effect of intracerebroventricular (ICV) administration of 20 µU of insulin (A) and 5 µg of CRF (B) on renal sympathetic nerve activity (RSNA) in control mice and db/db mice.
There was no significant change in MAP and HR after ICV administration of MTII, insulin, or CRF as compared with vehicle (data not shown).
Effects of MTII and CRF on RSNA in MC-4R knock-out mice
As shown in Table 2 and as expected from a previous report (Huszar et al., 1997
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Table 2. Different physiological parameters obtained from heterozygous and homozygous MC4R knock-out mice and their wild-type controls
To assess whether mice lacking the MC4-R exhibited an alteration in the RSNA response to MTII, we compared the effects of MTII on RSNA between homozygous and heterozygous mutant mice and their wild-type controls. As expected, ICV administration of 2 µg of MTII caused a significant increase in RSNA in the wild-type mice (299 ± 48% in the fourth hour; p < 0.001 vs vehicle), but MTII had no significant effect on RSNA in the homozygous MC-4R knock-out mice. The RSNA response to MTII in the heterozygous mutant mice was intermediate between the wild-type and homozygous mutant siblings [153 ± 31% in the fourth hour; p < 0.001 vs vehicle and p < 0.05 vs MC-4R (+/+) and MC-4R (-/-)]. However, lack of the MC4-R did not alter the RSNA response to ICV administration of 5 µg of CRF, because the renal sympathoactivation induced by CRF was comparable in wild-type and MC4-R knock-out mice (p = 0.78) (Fig. 4).
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Figure 4. Effect of ICV administration of 2 µg of MC-3/4R agonist (MTII) and 5 µg of CRF on renal sympathetic nerve activity (RSNA, mean of the fourth hour) in homozygous and heterozygous MC-4R knock-out mice as compared with their wild-type controls.
Effects of leptin and insulin on RSNA in MC-4R knock-out mice
To investigate the role of MC-4R in the RSNA response to leptin, we compared the effect of leptin on RSNA between wild-type mice and MC-4R knock-out mice. ICV administration of 2 µg of leptin increased RSNA in the wild-type mice (220 ± 45% in the fourth hour; p < 0.001 vs vehicle), but leptin had no significant effect on RSNA in the homozygous MC-4R knock-out mice (Fig. 5). A 10-fold higher dose (20 µg) of leptin did not affect RNSA in the null mutant mice (28 ± 22% in the fourth hour; n = 5; p = 0.58). As with the ICV injection of MTII, the RSNA response to ICV leptin in the heterozygous MC-4R knock-out mice was intermediate between the wild-type and the homozygous mutant mice [111 ± 19% in the fourth hour; p < 0.01 vs vehicle and p < 0.05 vs MC-4R (+/+)].
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Figure 5. Effect of intracerebroventricular (ICV) administration of 2 µg of leptin (A) and 20 µU of insulin (B) on renal sympathetic nerve activity (RSNA) in homozygous and heterozygous MC-4R knock-out mice as compared with their wild-type controls.
Next we examined the role of the MC4-R in the RSNA response to insulin. ICV administration of 20 µU of insulin induced a significant increase in RSNA in wild-type mice (190 ± 30% in the fourth hour; p < 0.001 vs vehicle) but not in the homozygous MC4-R knock-out mice (4 ± 11% in the fourth hour). Again, the heterozygous MC4-R knock-out mice exhibited an intermediate response to insulin [95 ± 22% in the fourth hour; p < 0.01 vs vehicle and p < 0.05 vs MC-4R (+/+) and MC-4R (-/-)].
In the MC-4R knock-out and wild-type mice, ICV administration of MTII, CRF, leptin, or insulin did not alter MAP and HR as compared with vehicle-treated mice (data not shown).
Discussion
The present study demonstrates that cerebroventricular administration of leptin and insulin in mice caused a significant increase in sympathetic nerve activity to the kidney, thus confirming previous reports (Muntzel et al., 1995The receptor-mediated sympathoexcitatory effect of leptin is also supported by the substantially decreased sympathetic response to leptin in the obese Zucker rats (Haynes et al., 1997
Our finding of a MC4-R gene dose effect on the RSNA response to MTII indicates the importance of this receptor in melanocortin control of sympathetic nerve activity. Furthermore, our results support a pivotal role for MC-4R in control of sympathetic nerve activity by leptin and insulin. Failure of leptin and insulin to increase RSNA in MC-4R knock-out mice cannot be attributed to obesity because the RSNA response to these hormones is preserved in obese mice such as the db/db mice for insulin (present study) and agouti obese mice for leptin (Correia et al., 2002
The attenuated RSNA response to stimulation of the melanocortin system in db/db mice was unexpected because melanocortin signaling is considered downstream to leptin receptors. Absence of leptin receptor might be expected to produce an exaggerated response to MTII caused by upregulation of the melanocortin receptors. We have no explanation for this attenuated RSNA response to MTII in db/db mice. Nonetheless, consistent with our findings, Benoit et al. (2000
We have reported previously that yellow obese agouti mice, in which it has been postulated that blockade of
In contrast to the high level of arterial pressure described in the agouti mice (Rahmouni et al., 2002
20-fold) is not followed by a similar increase in baseline RSNA, perhaps because of the reduced efficiency of CNS insulin uptake from plasma. Indeed, insulin is known to cross the blood–brain barrier by a specific and saturable mechanism, which appears to limit the access of this hormone to the brain when its circulating levels are increased (Figlewicz et al., 1985
Kaiyala et al., 2000
Our focus was on RSNA because renal nerves are the communication link between the CNS and the kidney, which is known to play a major role in the control of cardiovascular function (DiBona and Kopp, 1997
In conclusion, we have shown that intracerebroventricular administration of leptin, insulin, and MC-3/4R agonist (MTII) caused a significant increase in RSNA. Absence of the long form of the leptin receptor Ob-Rb in the db/db mice abolished the increase in RSNA induced by leptin and attenuated the sympathoexcitatory effect of MTII. This suggests that leptin activation of hypothalamic nuclei is required for renal sympathoactivation by the melanocortin system. Homozygous MC-4R knock-out mice have an absent RSNA response to MTII, leptin, and insulin, whereas the heterozygous MC-4R knock-out had an attenuated response to these stimuli. These findings indicate an important physiologic role for MC-4R in the regulation of renal sympathetic traffic by both leptin and insulin.
Footnotes
Received Feb. 12, 2003; revised May. 7, 2003; accepted May. 7, 2003.This work was supported by Grants HL 44546 and HL 14388 from the National Heart, Lung, and Blood Institute and by research funds from the Department of Veterans Affairs. K.R. was supported by a postdoctoral fellowship award (0120606Z) from the Heartland Affiliate of American Heart Association. W.G.H. was the recipient of the Pharmaceutical Research Manufacturers of America Faculty Development Award.
Correspondence should be addressed to Dr. Kamal Rahmouni, University of Iowa, Cardiovascular Center, 524 Medical Research Center, Iowa City, IA 52242. E mail: kamal-rahmouni{at}uiowa.edu.
Copyright © 2003 Society for Neuroscience 0270-6474/03/235998-07$15.00/0
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