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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3126-3131
Copyright © 2000 by The Endocrine Society

Original Studies

Hypertension in Obesity and the Leptin Receptor Gene Locus1

Roland Rosmond, Yvon C. Chagnon, Göran Holm, Monique Chagnon, Louis Pérusse, Kajsa Lindell, Björn Carlsson, Claude Bouchard and Per Björntorp

Department of Heart and Lung Diseases (R.R., G.H., P.B.) and Research Center for Endocrinology and Metabolism (K.L., B.C.), Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden; Physical Activity Sciences Laboratory (Y.C.C., L.P.), Laval University, Ste-Foy, Quebec G1K 7P4, Canada; and Pennington Biomedical Research Center (R.R., M.C., C.B.), Louisiana State University, Baton Rouge, Louisiana 70808

Address correspondence and requests for reprints to: Roland Rosmond, M.D., Ph.D., Department of Heart and Lung Diseases, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Recent animal studies indicate that leptin is involved in the regulation of blood pressure through the leptin receptor. Therefore, 51-yr-old men (N = 284) were selected; and anthropometric, endocrine, metabolic, and hemodynamic variables were examined in relation to polymorphisms of the leptin receptor gene (LEPR), by restriction fragment length polymorphism technique.

Three polymorphisms were examined: Lys109Arg in exon 4, Gln223Arg in exon 6, and Lys656Asn in exon 14. In comparison with Lys109 homozygotes, Arg109 homozygotes (9%) showed lower body mass index (BMI) and abdominal sagittal diameter, as well as lower systolic (10.0 mm Hg) and diastolic (7.8 mm Hg) blood pressure. Additionally, Arg223 homozygotes (26.8%) showed lower blood pressure (7.6/5.7 mm Hg) than Gln223 homozygotes. These lower blood pressure levels were independent of other variables. No differences were found with the Lys656Asn polymorphism.

Measurements of body fat mass correlated with leptin concentration in Lys109 homozygotes and in Lys109 heterozygotes but not in Arg109 homozygotes. Blood pressure correlated with leptin only in men carrying the wild-type allele Lys109. With both elevated BMI and leptin, Lys109 homozygotes had higher blood pressure than the Arg109 homozygous men (12.4/6.9 mm Hg). Men with blood pressure >= 140/90 mm Hg had, in comparison with normotensive men, increased BMI and leptin levels, and Lys109 homozygotes were significantly more prevalent.

These results suggest that leptin is associated with blood pressure regulation in men through the leptin receptor. When BMI and leptin are elevated, increased blood pressure is found only with the most prevalent LEPR genotype at codons 109 and 223, whereas variants of this receptor seem to protect from hypertension. This might explain why not all obese men are hypertensive.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ob GENE product leptin acts on the brain, through specific receptors, to suppress synthesis and secretion of neuropeptide Y, the most potent stimulator of food intake (1, 2). In addition, leptin may affect several of the major neuropeptides that affect eating (1, 2). Leptin has also extrahypothalamic functions, and potential sites of action correspond to the distribution of leptin receptor (3). Leptin is thought to play a role in the neuroendocrine regulation of reproduction, and leptin advances the puberty in normal female mice (4). Estrogen administration, in turn, increases the leptin levels, implying a coordinated, reciprocal regulation of sex steroids and leptin (5).

In addition to regulating satiety, leptin increases thermogenesis via sympathetic nervous system activity (6, 7). Leptin also increases norepinephrine turnover in brown adipose tissue (8), mainly by enhancing the sympathetic nerve activity in this tissue (9). Recent animal studies suggest that leptin also participates in the regulation of blood pressure (9). This is of interest because the sympathetic nervous system influences circulation, and the pathogenesis of essential (primary) hypertension is now generally considered secondary to activation of the central sympathetic nervous system in an early, hyperkinetic state (10, 11).

Obesity is associated with hypertension (12), possibly resulting from sympathetic nervous system activity (13). Obese humans have increased circulating levels of leptin (14); and given the associations with the sympathetic nervous system, this might contribute to the pathogenesis of hypertension in obesity. The diminished effect of leptin on satiety, manifested as a so-called leptin resistance, with maintained obesity despite elevated leptin concentrations, makes such a mechanism unlikely. However, one can not rule out the possibility that the leptin signal, via central leptin receptors, is specifically inhibited to pathways of satiety control but not to other functions, such as to the sympathetic nervous system.

With this background, exonic DNA sequence variations in the leptin receptor gene (LEPR), which may contribute to common forms of human obesity (15, 16), were examined in randomly selected men, in relation to several variables, including obesity and blood pressure. The results show that such polymorphisms are associated with low blood pressure, even in the presence of obesity and elevated leptin levels.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

In the present study, we recruited the subjects from an ongoing cohort study of men (N = 1302) born during the first 6 months of 1944 and living in G{varphi}teborg (17, 18). The study started in 1992. Based on self-measured waist-to-hip ratio (WHR), the following 3 subgroups, each of 150 men, were selected for further studies: the lowest (<=0.885) and the highest values (>=1.01), as well as men around the arithmetic mean (0.94–0.96). These men were examined in 1995 at the age of 51 yr (19, 20). A total of 284 (63.1%) volunteered to participate: 94 (62.7%) men with lowest, 94 (62.7%) with highest, and 96 (64.0%) around the mean value of WHR. None were excluded. The nonresponders did not differ, either in anthropometric, psychosocial, and socioeconomic variables or in somatic health status, from those participating. The study was conducted according to the principles expressed in the Declaration of Helsinki, and it was approved by the local ethics committee. Nine (3.2%) subjects refused to participate in the genetic studies. Further details about the study population have been reported previously (19, 20).

Phenotypic measurements

Body weight and height were measured, as well as circumferences and abdominal sagittal diameter, as described previously (19, 20).

Diurnal cortisol secretion was measured by a series of saliva sampling, over an ordinary working day, in which cortisol levels were measured. Additionally, a dexamethasone suppression test was done at home, using 0.5 mg or, in some cases (N = 40), 0.25 mg dexamethasone. The details of the procedures have been described previously (19, 20).

Venous blood was obtained after overnight fasting. Commercial RIA kits were used for the determination of serum testosterone, insulin-like growth factor I (IGF-I), insulin, and leptin. Glucose and serum lipids were determined enzymatically, as detailed previously (19, 20).

Two blood pressure readings were recorded on the right arm, with the participants sitting, using a random-zero mercury sphygmomanometer, after 5 min resting, with the auscultation site at heart level, a peak inflation level of 30 mm Hg above radial pulse disappearance, and a cuff-deflation rate of 2–3 mm Hg. Values were recorded to the nearest even digit. Heart rate was recorded simultaneously, and the individual mean systolic and diastolic blood pressures were calculated as the mean of the two measurements.

Determination of genotypes

DNA was extracted using a kit from QIAGEN Inc. GmbH, Hilden, Germany. The three restriction fragment length polymorphisms analyzed have been described previously (15, 16, 21). PCR was performed on a Perkin-Elmer 9600. For Lys109Arg and Gln223Arg, 100 ng of genomic DNA were amplified; while for Lys656Asn, 200 ng were used. The PCR for all the markers was performed using 200 µM of each dNTPs 300 µM of each primer and 0.5 U of Taq polymerase in its specific buffer (Amersham Pharmacia Biotech, Baie d’Urf{iota}, Quebec City, Canada) in a final vol of 10 µL. PCR conditions were 95 C, 3 min; 55 C, 1 min; 72 C, 1 min for 1 cycle, followed by 40 cycles at 95 C, 30 sec; 55 C, 30 sec; 72 C, 30 sec; and a final extension of 10 min at 72 C. PCR products were digested with 5 U of either HaeIII (exon 4), MspI (exon 6), or BstUI (exon 14) restriction enzyme (New England Biolabs, Inc., Mississauga, Ontario, Canada) at 37 C overnight (BstUI is an isoschizomer of MvnI originally used in Ref. 21). The generated fragments were separated on agarose gels (2.5% or 3%) and stained with ethidium bromide and a Polaroid photo was taken for genotyping.

Statistical analysis

Data comparisons were carried out with the Kruskall-Wallis H test [Spjotvoll-Stoline post hoc correction (22)]. The results are presented as mean ± SD. The Blomqvist median coefficient (23, 24) provides the correlation between pairs of variables, and the test of significance is based on the Fisher permutation test [Hommel post hoc correction (25)]. Multivariate analyses were performed with an ANCOVA model (26).

P values are two-sided throughout, and a P < 0.05 was considered significant. The statistical analyses were performed with SAS for Windows, release 6.12 (SAS Institute, Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go shows the results, in relation to Lys109Arg polymorphism, in exon 4. In comparison with the Lys109 homozygotes, Arg109 homozygotes showed lower body mass index (BMI), abdominal sagittal diameter, and systolic and diastolic blood pressures, with higher high-density lipoprotein (HDL) cholesterol and low triglycerides (borderline significance). Similar comparisons with heterozygotes showed a borderline significant difference, with less suppression of cortisol, with 0.25-mg dexamethasone in the heterozygotes. When heterozygotes were compared with Arg109 homozygotes, the latter had lower BMI and blood pressure. The blood pressure differences remained significant after adjustments for other variables, including anthropometric measurements and leptin.


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  		Table 1. Results of measurements in relation to the polymorphism Lys109Arg in exon 4

 
Table 2Go shows similar comparisons with Gln223Arg polymorphism in exon 6. Arg223 homozygotes had, in comparison with Gln223 homozygotes, higher HDL, lower triglycerides, and lower systolic and diastolic blood pressures. Similar comparisons with heterozygotes indicated remaining differences in triglycerides and HDL, whereas in comparisons between heterozygotes and Arg223 homozygotes, the latter had lower blood pressure. The blood pressure differences remained after adjustment for other variables.


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  		Table 2. Results of measurements in relation to the polymorphism Gln223Arg in exon 6

 
Comparisons between the genotypes for polymorphism Lys656Asn in exon 14 are presented in Table 3Go. Asn656 homozygous men were few (N = 8) and showed no differences, in comparison with Lys656 homozygotes. The heterozygotes showed no difference in comparison with the other groups.


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  		Table 3. Results of measurements in relation to the polymorphism Lys656Asn in exon 14

 
Correlation indices for the phenotypic variables measured were essentially identical across the different genotypes (not shown).

The correlations between leptin and anthropometric variables (BMI, WHR, and abdominal sagittal diameter) and systolic blood pressure in the different genotypes of the polymorphism in exon 4 are given in Table 4Go. Significant associations were found between leptin, on the one hand, and BMI, WHR, abdominal sagittal diameter, and blood pressure, on the other, in the Lys109 homozygotes. In heterozygotes, these correlations remained significant, except for blood pressure. In Arg109 homozygotes, these correlations were not significant.


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  		Table 4. The correlations (rm) between leptin and anthropometric measurement as well as systolic blood pressure in relation to the polymorphism Lys109Arg in exon 4

 
To see whether elevated BMI and leptin levels were associated with blood pressure in the different LEPR genotypes, men with both a BMI more than 25.7 and leptin more than 5.1 µg/L (median values) were first selected (N = 101). Blood pressure readings were then analyzed among homozygotes of the Lys109Arg and Gln223Arg polymorphisms (Table 5Go). In these men with elevated BMI and leptin, systolic blood pressure was significantly higher (12.4 mm Hg) in Lys109 (N = 161) than Arg109 (N = 24) homozygotes. In addition, leptin levels were significantly lower in Lys109 homozygotes. Similar differences in blood pressure between Gln223 and Arg223 homozygotes did not reach statistical significance. BMI was comparable among the groups.


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  		Table 5. Differences in blood pressure measurements, BMI, and leptin in subjects with both BMI > 25.7 kg/m2 and leptin > 5.1 µg/L, in relation to selected polymorphism in Lys109Arg and Gln223Arg

 
Next, BMI, leptin, and the distribution of genotypes of the polymorphism Lys109Arg were compared in men with and without elevated blood pressure. The blood pressure cutoffs were set to >=140/90 mm Hg for mild hypertension and <140/90 mm Hg for normal blood pressure (25). Men using antihypertensive drugs (n = 6; 2.1%) were included in the former group. Table 6Go shows that men with hypertension had significantly higher values of both BMI and leptin than normotensive men. Lys109 homozygotes were significantly more prevalent among the hypertensive men. In contrast, among hypertensive men, only three were Arg109 homozygotes, compared with about 11% in the normotensives. The frequency of heterozygotes was similar across the groups.


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  		Table 6. Differences in mean BMI and leptin, and also frequencies of the mutation Lys109arg in relation to systolic blood pressure (SBP), and diastolic blood pressure (DBP)

 
Finally, an analysis was performed to examine combined polymorphisms in relation to blood pressure (not shown in TableGo). These were significantly higher in the men with the alleles Lys109Lys–Gln223Gln than the Arg109Arg–Arg223Arg; 13.3 mm Hg in systolic and 10.4 mm Hg in diastolic blood pressure (P = 0.002).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The findings reported here are, to our knowledge, the first on polymorphism in the LEPR in relation to blood pressure in humans. The main findings are lower systolic and diastolic blood pressures among Arg109 and Arg223 homozygotes. The BMI and abdominal sagittal diameter were also lower in the Arg109Arg genotype. The differences in blood pressure remained significant after adjusting for the influence of obesity and body fat distribution, as well as insulin and leptin. The differences in blood pressure in the Arg109 and Arg223 homozygotes are considerable and most likely clinically important (10.0 and 7.6 mm Hg in systolic, and 7.8 and 5.7 mm Hg in diastolic blood pressure, respectively). When cross-tabulating Lys109 and Gln223 homozygotes with Arg109 and Arg223 homozygotes, these differences increased further to 13.3/10.4 mm Hg in systolic/diastolic blood pressure. No significant differences between genotypes with the mutation Lys656Asn were found. However, the number of Asn656 homozygotes were presumably too small (N = 8) to allow meaningful comparisons.

The examined men were selected from an ongoing cohort study, and 80% volunteered to participate in the first part of the study. The second part, which was laboratory-based, attracted fewer participants, but the nonresponders showed a structure similar to the responders in such a way that selection bias probably is negligible (19, 20).

As mentioned in the introduction, leptin is believed to interact with the central sympathetic nervous system (8, 9). In addition, blood pressure increases with infusion of leptin (27). Furthermore, transgenic mice overexpressing leptin have elevated blood pressure, normalized by {alpha}-adrenergic blockade (28). Considerable evidence thus indicates that leptin increases blood pressure through activation of the sympathetic nervous system. This leptin effect is most likely mediated through the central leptin receptors. Obese Zucker rats, which have a mutation in the LEPR, do not have increased sympathetic nervous system activity despite their associated obesity and elevated leptin and insulin levels, which would make them particularly prone to blood pressure elevation (29). These results then indicate that leptin increases blood pressure via the leptin receptor by activating the central sympathetic nervous system. Consequently, we can hypothesize that blood pressure rise is absent with a defective central leptin receptor.

The significant correlations between leptin and measurements of body fat (Table 4Go) confirm previous findings (14). This was found in men carrying the frequent LEPR genotype but not in the variant Arg109 homozygotes. This suggests that the coupling between leptin levels and body fat mass could be dependent on LEPR genotype. With the exception of a rare mutation in the LEPR (30), it has, however, not been possible to link elevated leptin levels to a defective leptin receptor in humans. Interestingly, recent data in rodents suggest that mutations in the leptin receptor system may have significant effects on adiposity (31, 32).

Blood pressure was related to leptin levels only in men with the most common LEPR allele [Blomquist median coefficient (rm) = 0.34, P < 0.001] (Table 4Go). This correlation was not observed in Lys109 heterozygotes or Arg109 homozygotes (rm = 0.03 and rm = 0.00, respectively). This indicates that blood pressure regulation by leptin is dependent on a wild-type LEPR and suggests that such regulation is signaled directly by the receptor.

In summary, these results suggest that when the LEPR is a variant form, the leptin–body fat mass relationship is disrupted, hypothetically by a perturbed interaction between overriding, parallel factors and the leptin system (21). The blood pressure regulation, however, seems to be directly dependent on the LEPR. If this interpretation is correct, LEPR polymorphisms might provide a protection against hypertension in obesity. Moreover, obese men with elevated leptin levels and the most frequent LEPR genotype would have higher blood pressure than men with a variant LEPR genotype. The results in Table 5Go show that this is indeed the case. The differences were 12.4 mm Hg in systolic and 6.9 mm Hg in diastolic blood pressure. Although the mean values in blood pressure (136.7/87.2 mm Hg; Table 5Go) may not be considered as hypertension, the mild hypertensive subjects (>=140/90 mm Hg) (33) are all found in this group. The blood pressure differences were further increased in men with polymorphisms in both exon 4 and exon 6, in comparison with men with the wild genotypes. In addition, men with mild hypertension had higher BMI and leptin, in combination with the most common LEPR alleles (Table 6Go).

A hyperkinetic state characterizes early primary hypertension in humans, which most likely is attributable to activation of the central sympathetic nervous system (10, 11). Subjects with early, hyperkinetic hypertension are often obese (12, 13). In analogy with available data (2, 3, 4), such obese subjects often have elevated circulating leptin levels (Table 6Go). The ability of signals from the leptin receptor to gain access to sites of action in the central sympathetic nervous system may increase the blood pressure. Thus, obese men with elevated leptin and the common LEPR genotypes may be those who are particularly prone to develop hypertension by amplification of signals to the central sympathetic nervous system from the leptin signaling pathway. This would also explain why not all obese subjects are hypertensive, because they might be protected by absence of signals from the leptin receptor when the gene for this receptor is variant, provided such variants produce a malfunctioning receptor. This polymorphism is prevalent in the population examined (about 9% for the Arg109 homozygotes and 27% for the Arg223 homozygotes). This possibility seems to be of sufficient interest to be further explored.


   Acknowledgments
 
We thank (in alphabetical order) Christina Jonsteg, George Lappas, Katarina Romanus, Erik Tengdahl, and Inga-Lill Ehs for excellent technical assistance. We also express our gratitude to Chantal Par{iota}, who did all the DNA extractions and the technical work at the Physical Activity Sciences Laboratory.


   Footnotes
 
1 Supported by grants from the Swedish Medical Research Council (K97-19X-00251-35A) and the Medical Research Council of Canada (MT-13960). Back

Received December 8, 1999.

Revised April 20, 2000.

Accepted May 9, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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