Published online before print July 18, 2005, doi: 10.1161/01.HYP.0000175474.99326.bf
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(Hypertension. 2005;46:326.)
© 2005 American Heart Association, Inc.
Original Articles |
Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Correspondence to Lakshmi S. Tallam, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505. E-mail ltallam{at}physiology.umsmed.edu
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Abstract |
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The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (–/–) and heterozygous (+/–) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (–/–) mice were severely obese compared with MC4R (+/–) and WT mice (body weight 48±1.5 versus 31±0.6 and 30±0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (–/–) 110±3 mm Hg; MC4R (+/–) 109±2 mm Hg; WT 114±2 mm Hg), and HR in MC4R (–/–) was lower than in WT (604±5 versus 645±9 bpm; P<0.05) but not different from MC4R (+/–) (625±13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (–/–) compared with MC4R (+/–) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (–/–) than in MC4R (+/–) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (–/–) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.
Key Words: obesity • insulin resistance • hypertension, sodium-dependent • arterial pressure • renin-angiotensin system
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Introduction |
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Evidence from epidemiological, clinical, and experimental studies has consistently demonstrated that obesity is a major cause of essential hypertension.1–3 Previous studies show that
/ß-adrenergic receptor antagonists and renal denervation significantly blunt the rise in arterial pressure associated with weight gain in diet-induced obese animal models, indicating that increased sympathetic nervous system (SNS) activation is an important cause of obesity-induced hypertension.3,4 However, the mechanisms that link SNS activation to the development of hypertension in obesity are still unclear.
One potential mechanism that could link obesity, SNS activation, and hypertension is the hypothalamic pro-opiomelanocortin (POMC) pathway. Several studies have indicated that the hypothalamic melanocortin system, acting through the melanocortin-3 receptor (MC3R) and MC4R, is a major regulator of energy balance. -Melanocyte–stimulating hormone (-MSH), the proteolytic byproduct of the POMC peptide, activates the hypothalamic MC3/4R to suppress appetite and to increase energy expenditure.5 Recent studies suggest that the hypothalamic melanocortin system may also be important in cardiovascular regulation. For example, acute intracerebroventricular injections of -MSH increase SNS activity to the kidneys,6 and chronic activation of MC3/4R raises arterial pressure in rats despite decreased food intake.7,8 The observed increase in blood pressure is mainly attributable to SNS activation because combined -adrenergic and ß-adrenergic receptor blockade completely abolished the rise in arterial pressure associated with MC3/4R activation.7 Furthermore, chronic blockade of MC3/4R in the central nervous system (CNS) for 12 days caused rapid weight gain but no increase in arterial pressure and a reduction in heart rate (HR).8 Because weight gain usually raises arterial pressure, these observations suggest that a functional MC3/4R may be necessary for excess weight gain to raise SNS activity and arterial pressure. However, it is unknown whether activation of MC3R or MC4R is more important in chronic cardiovascular regulation in obesity and whether specific blockade of MC4R would prevent increases in arterial pressure associated with obesity.
MC4R appears to be more important than MC3R in appetite regulation because targeted disruption of MC4R but not MC3R leads to hyperphagia and obesity.9,10 Furthermore, acute sympathoexcitation induced by malanotan-II, an MC3/4R agonist, was greatly attenuated in MC4R-deficient mice, suggesting that MC4R caused most of the SNS activation.11 However, the importance of MC4R in chronic cardiovascular regulation is unknown. The goal of the present study was to test the hypothesis that activation of MC4R is critical for the development of hypertension associated with obesity by examining the control of blood pressure in obese MC4R-deficient mice under basal conditions and in response to increased sodium intake.
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Methods |
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All experimental procedures and protocols conform to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the institutional animal care and use committee of the University of Mississippi Medical Center.
Breeding and Genotyping
MC4R-deficient mice were obtained from Dr Roger Cone of Oregon Health Sciences University. These mice were derived from the original colony of Huszar et al and maintained on the C57/BL6J background for 
10 generations.9,12 MC4R homozygous (–/–) and MC4R heterozygous (–/+) mice used in our studies were generated by breeding in our transgenic facility and genotyped by polymerase chain reaction (PCR) as described previously.13 All mice were maintained on a regular chow diet ad libitum and their weights monitored twice per week from 3 to 4 weeks to 18 weeks of age.
Surgical Protocol for Implantation of Telemetric Pressure Transmitter
Mice were anesthetized with sodium pentobarbital (50 mg/kg IP), and atropine sulfate (0.1 mg/kg) was administered to prevent excess airway secretions. The right common carotid artery was cannulated with the catheter of the pressure transmitter (Model TA11PAC40; Data Sciences International), and the transmitter body was placed in a subcutaneous pocket.
For 48 hours after surgery, mice were housed individually in shoebox cages and were allowed to recover on a warm heating pad. Mice were then moved to individual metabolic cages for determination of daily food and water consumption. After 10 days of recovery from surgery, we began monitoring mean arterial pressure (MAP) and HR continuously 24 hours per day using the telemetry data acquisition system (Data Sciences International). Mice received food and water ad libitum throughout the study and were placed on a 12-hour light/dark cycle.
Experimental Protocol
Three groups of 17- to 19-week-old male mice were used in this study (n=6 to 8 per group): wild-type (WT) C57BL/6J mice, MC4R (–/–) mice, and MC4R (+/–) mice. C57BL/6J mice were used as controls because MC4R-deficient mice were bred into the C57BL/6J genetic background for >10 generations. After 3 days of stable control measurements on a normal-salt diet (NSD; 0.4% NaCl; Test Diet), mice were placed on a high-salt diet (HSD; 4% NaCl diet; Test Diet) for 7 days, after which mice were returned to an NSD for 3-day postcontrol measurements. Twenty-four–hour MAP and HR and food and water intake were recorded daily.
At the end of the study, mice were fasted for 2 to 3 hours, anesthetized with isoflurane, and blood samples (200 µL) were collected by cardiac puncture for determination of plasma glucose, insulin, and leptin concentrations. Mice were then transcardially perfused with 0.1% PBS, and the heart, kidneys, and visceral fat were collected and weighed.
Kidney RNA Isolation and Real-Time RT-PCR for Renin, Angiotensin-Converting Enzyme, and Angiotensin Type-1 Receptor
Kidneys from a separate group of 17- to 19-week-old male MC4R (–/–) and WT mice (n=6 to 10 per group) were isolated and snap-frozen in liquid nitrogen and stored at –70°C for real-time RT-PCR analysis of whole-kidney mRNA expression for angiotensin-converting enzyme (ACE), renin, and angiotensin type-1 receptor (AT1R).
RNA was prepared from tissues using Tri-reagent per manufacturer instructions (Molecular Research Center). RNA was then treated with DNase to remove any contaminating DNA. First-strand synthesis was performed with the iScript cDNA Synthesis system (Bio-Rad). After the reverse transcription reaction, real-time PCR was performed using iQ SYBR Green Supermix. Samples were denatured at 95°C for 30 s, annealed at 60°C for 30 s, and extended at 72°C for 30 s for 35 cycles with fluorescent data being collected over the extension step. Data analysis was performed using Icycler IQ software (Bio-Rad). Expression of each target mRNA relative to 18srRNA was calculated on the basis of the threshold cycle (CT) as 2–
CT, where CT=CT,target–CT,18srRNA and normalized between controls and each experimental treatment group. The primer pairs used are shown in Table 1.
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Analytical Methods
Plasma insulin and leptin concentrations were determined by ELISAs (Linco Insulin ELISA kit and R & D leptin ELISA kit). Plasma glucose concentrations were determined using the glucose oxidation method (Beckman glucose analyzer 2).
Statistical Methods
The data are expressed as mean±SEM. Data obtained on a daily basis were analyzed using ANOVA with repeated measures. Comparisons between groups were performed using 1-way ANOVA, followed by the Bonferroni post hoc test or Student t test where appropriate. Statistical significance was accepted at a level of P<0.05.
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Results |
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Weight Gain in MC4R-Deficient Mice
All 3 groups of mice had similar body weight at 3 weeks of age. After 4 weeks of age, the MC4R (–/–) mice were slightly heavier than the other 2 groups of mice. At 7 weeks of age, the body weights of the MC4R (–/–) mice were 20% greater than that of MC4R (+/–) and WT mice. The body weights of the MC4R (+/–) mice tended to be greater than that of WT mice from 12 weeks of age but were not significantly different. By 18 weeks of age, the body weight of MC4R (–/–) mice was 50% and 60% greater than that of MC4R (+/–) and WT mice, respectively (Figure 1). The average body weights of 17- to 19-week-old mice used in the present study are displayed in Table 2.
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Body Length, Visceral Fat, Food Intake, Water Intake, and Hormones
The mean length (naso-anal distance) of MC4R (–/–) mice at 17 to 20 weeks of age was 
8% greater than in MC4R (+/–) and WT mice, suggesting a role for MC4R in regulating linear growth. Parallel to the increase in body weight, MC4R (–/–) mice had 5- to 7-fold greater epididymal and retroperitoneal fat compared with MC4R (+/–) or WT mice. Despite similar body weights in MC4R (+/–) and WT mice, MC4R (+/–) had 75% more retroperitoneal fat than WT mice.
Basal food intake in MC4R (–/–) mice was 25% greater than in MC4R (+/–) and WT mice and was not altered by changes in salt intake. A 4% NaCl diet increased water intake in all groups (WT from 3.9±0.2 to 7.6±0.3 mL; MC4R (+/–) from 3.5±0.1 to 7.7±0.3 mL; and MC4R (–/–) from 4.8±0.1 to 11.3±0.3 mL). Plasma leptin levels in MC4R (–/–) mice were several-fold greater than in MC4R (+/–) and WT mice. Plasma insulin and glucose levels in MC4R (–/–) were also significantly increased compared with MC4R (+/–) and WT mice (Tables 2 and 3
).
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Arterial Pressure and HR During NSD
As shown in Figure 2, despite significantly greater body weight and visceral adiposity in MC4R (–/–) mice, the basal 24-hour average MAP measured on days 11, 12, and 13 after surgery in MC4R (–/–) mice (110±3 mm Hg) were not significantly different compared with MC4R (+/–) (109±2 mm Hg) and WT mice (114±2 mm Hg). However, daytime and 24-hour average MAP tended to be lower in the MC4R-deficient mice compared with the WT mice, and these differences were eliminated at nighttime (Figures 2, 3, and 4). Basal average 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP) were slightly but not significantly greater in WT mice compared with MC4R (–/–) and MC4R (+/–) mice (WT 129±3/98±3 mm Hg; MC4R (+/–) 124±4/94±6 mm Hg; MC4R (–/–) 125±6/96±9 mm Hg).
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Basal 24-hour average HR and daytime and nighttime HR measured on days 11, 12, and 13 after surgery in MC4R (–/–) mice (24-hour 604±5 bpm; daytime 596±7 bpm; nighttime 619±6 bpm) were significantly lower compared with WT mice (24-hour 645±9 bpm; daytime 631±14 bpm; nighttime 651±6) but not significantly different from MC4R (+/–) (24 hour 625±13 bpm; daytime 620±11; nighttime 647±10) (Figures 2 through 4
).
Effect of HSD on Arterial Pressure and HR
HSD (4% NaCl) feeding for 7 days did not significantly alter arterial pressure (MAP, SBP, DBP) during daytime or nighttime in any of the 3 groups of mice, as shown in Figures 3 and 4 (data not shown for SBP and DBP). HSD for 7 days did not significantly alter HR in either group of MC4R-deficient mice. However, in the WT mice, there was a slow fall in 24-hour average HR and daytime and nighttime HR, but this was not related to the high-salt treatment. Significant reductions in HR in WT mice were observed only on day 7 that were maintained during recovery, and this was primarily because of unexplainable decreases in HR in 2 mice during the last 4 days of the study.
Real-Time RT-PCR for Whole-Kidney Renin, ACE, and AT1R
Renal renin and AT1 mRNA expressions were 2- and 3-fold greater, respectively, in MC4R (–/–) compared with WT mice, whereas ACE mRNA expression was several-fold lower in MC4R (–/–) compared with WT mice (Figure 5).
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Discussion |
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The main finding of the present study is that MC4R (–/–) mice are neither hypertensive nor salt sensitive despite having several characteristics of the metabolic syndrome, including obesity, hyperinsulinemia, and hyperleptinemia, which usually tend to raise arterial pressure and HR. These findings are consistent with the hypothesis that a functional MC4R may be necessary for obesity to cause hypertension.
Metabolic Consequences of MC4R Deficiency
MC4R (–/–) mice were severely obese at maturity, as reported previously by other investigators.9 In our colony of mice, although MC4R (–/–) mice were 60% heavier at 17 weeks of age compared with WT mice, MC4R (+/–) mice were only 8% heavier than WT mice, suggesting that presence of 1 copy of the MC4R gene can significantly blunt the development of obesity. The increase in body weight with MC4R deficiency is primarily attributable to increased food consumption, although hypometabolism may also contribute to obesity with deletion of MC4R.14 Our observation that MC4R (+/–) mice have 30% greater visceral fat despite similar food intake when compared with WT mice suggests an important role for MC4R in regulating metabolism. Consistent with a gene-dosage effect, MC4R (–/–) mice had greater visceral fat compared with MC4R (+/–) mice, and MC4R (+/–) mice had significantly more visceral fat than WT mice.
In addition to increased body weight and visceral adiposity, MC4R (–/–) mice have several other characteristics of the metabolic syndrome. MC4R (–/–) mice are characterized by marked hyperinsulinemia and slight hyperglycemia, suggesting the development of insulin resistance at 17 to 19 weeks of age, as also reported previously.9 The development of insulin resistance may be related, at least in part, to the direct role of MC4R in regulating insulin sensitivity because central MC3/4R activation was shown previously to increase insulin sensitivity.8,15 Proportional to the increase in fat mass, the MC4R (–/–) mice had several-fold greater plasma leptin levels compared with WT mice. The presence of hyperphagia in MC4R (–/–) mice despite high circulating levels of leptin suggests that MC4R may mediate most of the appetite suppressant actions of leptin. However, it is also possible that MC4R (–/–) may have developed some resistance to the anorexic actions of leptin because of obesity. Supporting this view, Marsh et al report that young 5-week-old nonobese MC4R (–/–) mice were sensitive, whereas 12- to 13-week-old obese MC4R (–/–) mice were resistant to the anorexic actions of leptin.13
Cardiovascular Consequences of MC4R deficiency
Despite obesity, hyperleptinemia, and hyperinsulinemia, homozygous MC4R (–/–) mice were not hypertensive. In fact, chronic 24-hour MAP and HR measured several days after recovery from surgery using telemetry were lower in MC4R (–/–) compared with WT mice. MC4R (+/–) mice had an HR intermediate to that observed in MC4R (–/–) and WT mice, suggesting a gene-dosage effect. These data are consistent with our previous studies in rats in which chronic blockade of MC3/4R in the CNS for 12 days using SHU9119, a synthetic MC3/4R antagonist, caused pronounced obesity but prevented increases in MAP normally associated with excess weight gain and markedly decreased HR.8 We also showed that chronic central MC3/4R activation increases MAP and HR.7 However, our previous studies were not able to determine the separate roles of MC3R and MC4R in cardiovascular regulation in obesity. Results from our present study indicate that MC4R deficiency causes several characteristics of the metabolic syndrome, including insulin resistance, visceral fat accumulation, and hyperleptinemia, but no hypertension, suggesting that an intact MC4R may be necessary for obesity to cause hypertension. Alternatively, it is possible that obesity and the metabolic syndrome in the mouse are not associated with hypertension. However, several studies report increases in blood pressure during the development of obesity in mice. In WT mice and normal rats that have a functional MC4R, obesity produced by feeding a high-fat diet is accompanied by elevations in arterial pressure.16,17 Ortlepp et al reported that New Zealand obese mice that exhibit a polygenic obesity syndrome associated with hyperinsulinemia, hyperglycemia, and dyslipidemia also have an increase in arterial pressure that parallels weight gain.18 Another obese mouse model produced by transgenic reduction of brown fat that is hyperinsulinemic and dyslipidemic was also reported to be hypertensive compared with control animals.19 Our data, together with previous reports, suggest that obesity and the metabolic syndrome in mice with a functional MC4R are associated with increased blood pressure. Thus, a functional MC4R may be necessary for obesity to raise arterial pressure.
Previous studies suggest that hyperleptinemia, hyperinsulinemia, and visceral adiposity may raise arterial pressure and contribute to hypertension in obesity through SNS activation.20–22 Hence, the absence of hypertension in MC4R (–/–) mice despite hyperleptinemia, hyperinsulinemia, and visceral adiposity raises 2 important questions. The first is whether these factors are important in raising arterial pressure in obesity, and the second is whether MC4R is necessary for mediating their sympathoexcitatory and pressor actions. We showed previously that chronic increases in circulating leptin, similar to that found in severe obesity, raises arterial pressure and HR in rats.20,23 In addition, transgenic mice overexpressing leptin are hypertensive, whereas obese rodents or humans having deficiency in leptin secretion or leptin receptor mutations are protected from hypertension, suggesting that leptin may be an important link between obesity and hypertension.24–26 Emerging evidence, especially in humans, indicates that visceral fat accumulation raises arterial pressure.22 Alvarez et al demonstrated that muscle sympathetic nerve activation was 55% greater in patients with high abdominal visceral fat compared with patients with low abdominal visceral fat, suggesting that visceral fat can contribute to SNS activation in obesity.22 On the other hand, the role of insulin in raising arterial pressure in obesity is still unclear. We have shown recently that chronic CNS elevation of insulin to pathophysiological levels, as found in obesity, does not lead to a sustained increase in arterial pressure in rats, and chronic infusion of insulin in dogs actually reduces blood pressure.27,28 However, current evidence suggests that hyperleptinemia and visceral fat accumulation may be important in linking obesity with sympathetic activation and hypertension.
If leptin, visceral fat accumulation, and MC4R are all important in contributing to SNS activation and hypertension associated with obesity, then it is possible that MC4R mediates the sympathoexcitatory actions of leptin and visceral adiposity. Several pieces of evidence suggest that MC4R may mediate the pressor actions of leptin and thereby obesity hypertension. Hypothalamic POMC neurons express leptin receptors, and leptin binding to these receptors increases POMC expression, the precursor of -MSH, which, in turn, is the endogenous agonist of MC3/4R.29 Rahmouni et al demonstrated that MC4R (–/–) mice are resistant to the acute sympathoexcitatory actions of leptin.11 Furthermore, we have shown recently that increases in arterial pressure and HR induced by chronic elevation of circulating leptin to levels similar to that found in obesity can be inhibited by central MC3/4R blockade, suggesting an important role for the central MC3/4R in mediating the actions of leptin.30 Similarly, our current data demonstrating absence of hypertension in MC4R (–/–) mice despite hyperleptinemia also suggests that MC4R may be a key mediator of the cardiovascular actions of leptin. However, the importance of visceral fat in contributing to SNS activation and whether MC4R is also a mediator of these actions remains to be investigated.
Effect of HSD (4% NaCl) on Cardiovascular Function in MC4R (–/–) Mice
Several clinical and experimental studies have demonstrated the phenomenon of salt-sensitive hypertension in obesity, which may be attributed to multiple mechanisms including abnormal regulation of the renin-angiotensin-aldosterone (RAAS) system, SNS activation, and impaired renal function.31–33 However, we found that MC4R (–/–) mice, which have most of the characteristics of the metabolic syndrome, including obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, do not develop hypertension when fed an NSD or HSD. Moreover, arterial pressure in MC4R (–/–) mice failed to increase in response to an HSD despite 40% greater sodium intake (resulting from hyperphagia) when compared with WT mice. These data suggest that MC4R (–/–) mice have a normal pressure natriuresis relationship despite obesity. One explanation for the lack of salt sensitivity of blood pressure may be reduced MC4R-mediated SNS activation in MC4R (–/–) obese mice. Although it is possible that a longer duration of HSD could lead to the development of salt-sensitive hypertension in MC4R (–/–) mice, previous studies have been able to demonstrate the development of salt-sensitive hypertension within 7 to 10 days of treatment with HSD in other models like MC3R (–/–) mice and obese Zucker rats.34,35 However, the salt sensitivity of the MC3R (–/–) mice has been attributed primarily to the absence of the natriuretic actions of 
-MSH, mediated by the renal MC3R and not obesity because these mice are only mildly obese (10% overweight compared with WT), unlike the MC4R (–/–) mice. Absence of salt sensitivity in MC4R (–/–) mice suggests that renal MC4R, if present in mice kidneys, does not protect against salt sensitivity of blood pressure. Mountjoy et al36 reported only mild expression of MC4R in the adult rat kidney, and there have been no studies to our knowledge on renal MC4R expression in mice.
Because impaired regulation of the RAAS is considered to be very important in mediating salt-sensitive hypertension, we also measured whole-kidney mRNA by real-time RT-PCR for renin, ACE, and AT1R in MC4R (–/–) and WT mice on an NSD. The pronounced decrease in ACE gene expression despite increases in renal renin mRNA in MC4R (–/–) mice compared with WT mice suggests that renal angiotensin II levels may be suppressed in the MC4R (–/–) mice. It is possible that decreased angiotensin II levels are responsible for the 3-fold increase in AT1R gene expression in MC4R (–/–) mice compared with WT mice because receptor density is usually regulated in inverse proportion to the endogenous agonist concentrations. These data are consistent with our observation that blood pressure is not salt sensitive in MC4R (–/–) mice. Whether older MC4R (–/–) mice have impaired RAAS regulation and are salt sensitive remains to be determined. The absence of hypertension and salt sensitivity of blood pressure in the MC4R (–/–) mice also suggests that these mice may not have major renal damage despite obesity. Because obesity has been proposed to increase the risk for renal injury,37 future studies are needed to test whether MC4R (–/–) mice are protected from developing renal injury despite obesity.
Perspectives
Our data in obese MC4R-deficient mice indicate that hypertension associated with obesity may occur only in the presence of a functional MC4R. Although our data are consistent with the hypothesis that metabolic disorders such as visceral adiposity and hyperleptinemia may mediate their pressor actions via MC4R in the CNS, this hypothesis needs to be investigated further. Future studies are needed to address whether development of hypertension in response to obesity induced by high-fat diet is blunted in MC4R-deficient mice and whether attenuated SNS activation to the kidney contributed to the normotensive phenotype despite severe obesity and metabolic dysfunction in the MC4R (–/–) mice. If MC4R is essential for sympathetic activation in obesity, humans with mutations in MC4R may be protected from hypertension despite severe early-onset obesity and other metabolic disturbances as long as their kidneys have no pathological alterations. Although the present study highlights the importance of the central MC4R in contributing to obesity hypertension, the possible involvement of MC4R in normal regulation of sympathetic activity and blood pressure is also an important area for future investigation.
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Acknowledgments |
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Research was supported by National Heart, Lung and Blood Institute grant PO1HL-51971. L.S.T. was supported by a postdoctoral fellowship from the American Heart Association.
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Footnotes |
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This paper was sent to Ernesto L. Schiffrin, associate editor, for review by expert referees, editorial decision, and final disposition.
Received February 22, 2005; first decision March 15, 2005; accepted June 17, 2005.
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