Plasma Leptin and Blood Pressure in Men: Graded Association Independent of Body Mass and Fat Pattern Gianvincenzo Barba,* Ornella Russo,† Alfonso Siani,* Roberto Iacone,† Eduardo Farinaro,‡ Maria Clara Gerardi,† Paola Russo,* Elisabetta Della Valle,‡ and Pasquale Strazzullo†
Abstract BARBA, GIANVINCENZO, ORNELLA RUSSO, ALFONSO SIANI, ROBERTO IACONE, EDUARDO FARINARO, MARIA CLARA GERARDI, PAOLA RUSSO, ELISABETTA DELLA VALLE, AND PASQUALE STRAZZULLO. Plasma leptin and blood pressure in men: graded association independent of body mass and fat pattern. Obes Res. 2003; 11:160 –166. Objective: The role of leptin in the association between body mass, central adiposity, and blood pressure (BP) is controversial. This study evaluated the relationship between leptin and BP in relation to body mass index (BMI) and fat distribution in a large sample of untreated male adults. Research Methods and Procedures: The study population was made up of 457 untreated male employees of the Olivetti factory in Naples. Plasma leptin, complete anthropometry, BP, and relevant biochemical variables were measured. Results: Log-transformed plasma leptin levels were directly associated with BMI (r ⫽ 0.661, p ⬍ 0.001) and waist circumference (r ⫽ 0.630; p ⬍ 0.001). Leptin also correlated with systolic (r ⫽ 0.258) and diastolic (r ⫽ 0.277) BP (p ⬍ 0.001). The association between leptin and BP was maintained after accounting for age, BMI (or waist circumference), log-insulin, and serum creatinine (p ⬍ 0.01); this association was stronger than that with BMI. Logistic re-
Received for review February 25, 2002. Accepted for publication in final form October 29, 2002. *Epidemiology and Population Genetics, Institute of Food Science, National Research Council, Avellino, Italy; †Department of Clinical and Experimental Medicine, Unit of Clinical Genetics and Pharmacology, Hypertension and Mineral Metabolism, “Federico II” University of Naples Medical School, Naples, Italy; ‡Department of Preventive Medical Sciences, “Federico II” University of Naples Medical School, Naples, Italy. Address correspondence to Pasquale Strazzullo, M.D., Department of Clinical and Experimental Medicine, Federico II University of Naples Medical School, Via S. Pansini, 5, 80131 Naples, Italy; or to Gianvincenzo Barba, M.D., Epidemiology and Population Genetics, Institute of Food Science, CNR, Via Roma 52, AC-83100 Avellino, Italy. E-mail:
[email protected] or
[email protected] Copyright 2003 NAASO
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gression analysis showed that an increased prevalence of hypertension (BP ⱖ 140 and/or 90 mm Hg) was associated with high plasma leptin levels when controlling for age and waist circumference (odds ratio, 1.99; 95%CI, 1.06 to 3.72) or for age and BMI (odds ratio, 1.92; 95%CI, 1.02 to 3.61). Discussion: A graded positive relationship between plasma leptin levels and BP was observed in this sample of untreated male adults. This association was independent of age, BMI, abdominal adiposity, and fasting plasma insulin. Moreover, elevated plasma leptin concentrations were associated with greater probability of hypertension, again independently of potential confounders. Key words: leptin, hyperleptinemia, high blood pressure, total and central adiposity
Introduction Although the association of excess body weight with elevated blood pressure (BP)1 has been known for a long time (1,2), the pathophysiological bases of this association are not completely understood. A role for sympathetic nervous system overactivity and/or insulin resistance has been proposed based on clinical and experimental findings (3–5). More recently, attention has been paid to the possible role of leptin, a peptidic hormone involved in the regulation of food intake and satiety, as well as in the control of fat accumulation (6). Leptin depresses appetite and inhibits fat deposition, particularly in visceral depots, and at least part of its effects are mediated by sympathetic nervous system activation (7). Human obesity is characterized by elevated plasma leptin levels and “resistance” to the metabolic effects of the hormone to the extent that high plasma leptin levels are ineffective in reducing fat accumulation (8). It is conceiv-
1 Nonstandard abbreviations: BP, blood pressure; BMI, body mass index; HOMA, homeostatic assessment model.
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able, however, that leptin-mediated sympathetic activation in the circulatory district and/or at the renal level may affect blood pressure control and contribute to the occurrence of obesity-associated hypertension (5,9). Noteworthy, in ob/ob obese mice, in which plasma leptin levels are not detectable, BP is normal (10), whereas obese transgenic mice overexpressing plasma leptin are more prone to developing hypertension compared with wild-type animals (10,11). In humans, the strong interrelation between leptin, body mass index (BMI), and other measures of body fat have made it difficult to investigate the possible influence of the peptide on BP (8,12–14). Moreover, in most previous studies, limitations given by small sample size, patient selection, and ongoing pharmacological therapy have affected the interpretation of results. Population-based studies may not suffer from these limitations and may help to establish whether or not the putative association between hyperleptinemia and high BP is independent of the level of adiposity, body fat distribution, and age, as all these factors are, in turn, positively associated with BP. We thus sought to analyze this association in a large sample of untreated male workers who participated in a survey of cardiovascular risk factors in southern Italy (The Olivetti Heart Study) and from whom extensive anthropometrics, BP measurements, and relevant biochemical data were available.
Research Methods and Procedures Population The study was performed at the Olivetti factories of Pozzuoli (Naples) and Marcianise (Caserta) and was part of an investigation on the prevalence of cardiovascular risk factors in southern Italy involving the participation of the Olivetti factory male workforce. The methodology of the study has been described in detail previously (15,16). Between May 1994 and December 1995, a cohort of 1079 men in the age range of 25 to 75 years (51.8 ⫾ 7.5 years) were examined. They represented over 95% of the male workforce employed at the time. For the purpose of this study, 457 subjects were randomly selected from the study cohort after exclusion of individuals on regular dietary or pharmacological treatment for any cause. The local Ethics Committee approved the study protocol, and participants gave their informed consent to participate. Examination Procedures All examinations were performed between 8:00 AM and 11:00 AM in a quiet and comfortable room within the medical centers of the Pozzuoli and Marcianise factories, with the participants having fasted for at least 13 hours. The subjects were allowed to pursue their normal activities but were discouraged from engaging in vigorous exercise and were asked to abstain from smoking and from drinking alcohol, coffee, tea, and other beverages containing caffeine
during the morning of the study. The study included a physical examination and anthropometric measurements, a resting 12-lead electrocardiogram, a blood test, a fasting timed urine collection, and the administration of a questionnaire including information on medical history, working and leisure time physical activity, and dietary, drinking, and smoking habits. Anthropometry. Body weight and height were measured on a standard beam balance scale with an attached ruler. Body weight was measured to the nearest 0.1 kg, and body height was measured to the nearest 1.0 cm, with subjects wearing light indoor clothing without shoes. BMI was calculated according to the standard formula. The waist circumference, taken as an index of abdominal adiposity, was measured at the umbilicus level with the subject standing erect with abdomen relaxed, arms at the sides, and feet together; measurements were performed at the nearest 0.1 cm with a flexible inextensible plastic tape. BP Measurement. After the subject had been sitting for at least 10 minutes, systolic and diastolic (phase V) BP were taken three times 2 minutes apart with a random zero sphygmomanometer (Gelman Hawksley Ltd., Sussex, UK). The average of the second and third reading was recorded. Hypertension was defined as BP ⱖ140 and/or 90 mm Hg. Resting, supine heart rate was measured by electrocardiogram recording. Both anthropometric and BP measurements were performed by professional operators who had attended training sessions for standardization of the procedures. The operator code was recorded to check for possible measurement biases. Blood Sampling and Biochemical Assays A fasting venous blood sample was taken in the seated position between 8:00 AM and 10:00 AM, after the BP measurements, for determination of plasma leptin and serum insulin, lipids, glucose, creatinine, and sodium levels. The blood specimens were immediately centrifuged and stored at –70 °C until analyzed. Plasma leptin levels were measured by an enzyme-linked immunosorbent assay (R&D System GmbH, Wiesbaden-Nordenstadt, Germany). Serum cholesterol, triglyceride, and glucose levels were measured with automated methods (Cobas-Mira, Roche, Italy), creatinine by the picric acid colorimetric method, and serum and urinary electrolytes by atomic absorption spectrophotometry. Serum insulin was determined by radioimmunoassay (Insulin Lisophase; Technogenetics, Milan, Italy). The homeostatic assessment model (HOMA) index was used to estimate insulin resistance and calculated as fasting serum insulin (U/mL) ⫻ fasting serum glucose (mM)/22.5, as described by Matthews et al. (17). Statistical Analysis Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS-PC, version 10; OBESITY RESEARCH Vol. 11 No. 1 January 2003
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Table 1. Characteristics of the study sample (n ⫽ 457)
Age (years) Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min) BMI (kg/m2) Serum glucose (mM) Serum insulin (U/mL) Serum creatinine (M) Plasma leptin (ng/mL)
Table 2. Stepwise multiple regression analysis: blood pressure and selected variables
Mean (SD)
Range
50.9 ⫾ 7.4 127 ⫾ 15 83 ⫾ 9 62 ⫾ 9 26.8 ⫾ 3.1 5.42 ⫾ 0.69 9.23 ⫾ 6.96 92.2 ⫾ 10.4 4.11 ⫾ 2.79
25 to 73 90 to 180 62 to 111 40 to 120 19.0 to 37.0 2.50 to 9.16 1.14 to 99.8 42.7 to 176.4 0.46 to 21.7
SPSS, Inc., Chicago, IL). Because the distributions of leptin and insulin deviated significantly from normal, they were normalized by log-transformation, and log-transformed values were used in the analysis. Pearson’s correlation analysis was used to detect associations between selected variables. Stepwise multiple linear regression was used to determine the role of leptin as predictor of BP accounting for potential confounders as specified in the text. Logistic regression analysis was used in the whole sample to estimate the odds ratio of a given morbid condition (hypertension) according to plasma leptin and controlling for confounders. Student’s t test for unpaired data was used to assess differences between group means. Results were expressed as mean ⫾ SD or 95%CIs, unless otherwise indicated. Two-sided p values ⬍0.05 were considered statistically significant, unless otherwise indicated.
Results The study population was composed of 457 untreated men whose characteristics are reported in Table 1. Thirty percent of the participants were hypertensive; the large majority (70%) were overweight (BMI ⬎ 25 kg/m2), and 16% were obese (BMI ⬎ 30 kg/m2). Log-transformed plasma leptin levels were significantly and directly associated with BMI (r ⫽ 0.661, p ⬍ 0.001) and waist circumference (r ⫽ 0.630, p ⬍ 0.001). They were also significantly and directly associated with blood pressure (systolic BP: r ⫽ 0.258, diastolic BP: r ⫽ 0.277, p ⬍ 0.01) and with log-serum insulin (r ⫽ 0.186, p ⬍ 0.01). A step-wise multiple regression model was used to estimate the relative role of plasma leptin as predictor of BP accounting for waist circumference, serum insulin, and age. This analysis showed a significant association between plasma leptin and BP when taking these confounders into account (Table 2). According to the model, an increase in log-leptin of as much as 1 SD (corresponding to 3.02 ng/mL increase in plasma 162
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Covariates Dependent variable Systolic BP Waist circumference Age Log-leptin Log-insulin Creatinine Diastolic BP Waist circumference Log-leptin Age Log-insulin Creatinine

SE
T
p
0.467 0.454 9.49 not not
0.083 0.092 3.07 entered entered
5.65 4.92 3.09 at p ⬍ at p ⬍
⬍0.0001 ⬍0.0001 ⬍0.001 0.05 0.05
0.316 4.84 0.146 not not
0.05 1.89 0.06 entered entered
6.36 2.56 2.60 at p ⬍ at p ⬍
⬍0.001 ⬍0.01 ⬍0.01 0.05 0.05
leptin levels) was associated with an estimated increase in systolic and diastolic BP of 2.7 and 1.4 mm Hg, respectively (Figure 1). The inclusion of heart rate in the model attenuated the effect of plasma leptin, which remained, however, statistically significant (systolic BP:  ⫽ 11.97 ⫾ 2.33; T ⫽ 5.12; diastolic BP:  ⫽ 3.99 ⫾ 1.84; T ⫽ 2.83; p ⬍ 0.01 for both systolic BP and diastolic BP). The results did not substantially change when replacing waist circumference with BMI in the model (systolic BP:  ⫽ 13.26 ⫾ 2.36, T ⫽ 5.62, p ⬍ 0.001; diastolic BP:  ⫽ 5.07 ⫾ 1.95, T ⫽ 2.60, p ⬍ 0.01). Even when BMI and waist circumference were simultaneously added as covariates (although the high degree of colinearity of these two variables might affect the reliability of the results), plasma leptin maintained a significant influence on systolic BP ( ⫽ 10.37 ⫾ 3.20, T ⫽ 3.24, p ⫽ 0.001) and diastolic BP ( ⫽ 4.77 ⫾ 1.96, T ⫽ 2.43, p ⫽ 0.015). When only normotensive subjects (n ⫽ 319) were considered, the association between plasma leptin and blood pressure was still apparent independently of age and BMI (systolic BP: T ⫽ 3.57; diastolic BP:T ⫽ 4.80; p ⬍ 0.001 for both). To further evaluate the relationship between leptin and blood pressure accounting for overweight, we selected from the whole population two subgroups of age- and BMImatched overweight subjects with different plasma leptin levels, drawn from the uppermost tertile (n ⫽ 25; plasma leptin ⬎ 4.66 ng/mL) and the lowest tertile of plasma leptin (n ⫽ 25; plasma leptin ⬍ 2.66 ng/mL). The characteristics of the two groups are shown in Table 3. By definition, the two groups were similar by age and BMI. A statistically significant and clinically relevant difference in blood pressure was observed between the two groups; the participants
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Table 3. Comparison of age- and BMI-matched overweight participants with different plasma leptin levels Low leptin High leptin (I tertile) (III tertile)
Figure 1: Trends in systolic and diastolic BP according to plasma leptin distribution and levels. Linear regression line of BP on log-leptin after adjustment for age and waist circumference. Each point represents the estimated BP value corresponding to the mean log-leptin concentration for the population and for log-leptin 1 or 2 SDs above or below the median. The corresponding actual plasma leptin levels are also reported.
with high plasma leptin levels had significantly higher systolic and diastolic BP in comparison with similarly overweight individuals with lower plasma leptin. Resting heart rate and serum creatinine also tended to be higher in the group with elevated leptin levels (Table 3). Logistic regression analysis, performed on the entire population, was applied to assess the risk of being hypertensive depending on leptin levels and accounting for age and adiposity indexes. In a model including plasma leptin tertile, age, and waist circumference as covariates, a stepwise increase in the risk of hypertension was observed (Figure 2A) across tertiles of plasma leptin: odds ratio (OR) (95%CI) ⫽ 1.18 (0.67 to 2.08) and 1.99 (1.06 to 3.72), respectively, for the second vs. the first tertile and for the third vs. the first tertile. Similar results were obtained when waist circumference was replaced by BMI (Figure 2B) in the logistic regression model: OR (95% CI) ⫽ 1.16 (0.66 to 2.05) and 1.92 (1.02 to 3.61), respectively, for the second vs. the first tertile and for the third vs. the first tertile.
Discussion The investigation of the relationship between plasma leptin and BP in animal models (9,11,18) and in humans (8,19 –27) has so far been elusive. On the one hand, experimental studies have shown that leptin may reduce blood pressure through interactions with the nitric oxide pathway (28) and/or through a direct natriuretic effect (29). On the other hand, it has been suggested that leptin could have a prohypertensive effect (7,30,31). Shek et al. (9), using systemic intravenous leptin infusion, and, more recently, Cor-
N Age (years) BMI (kg/m2) Waist (cm) Leptin (ng/mL) Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/min) Serum insulin (U/mL) HOMA index Serum creatinine (M)
p*
25 49.7 ⫾ 5.4 27.0 ⫾ 1.6 93.8 ⫾ 3.7 2.01 ⫾ 0.50 123 ⫾ 16
25 50.0 ⫾ 5.3 NS 27.0 ⫾ 1.6 NS 95.6 ⫾ 4.2 NS 5.55 ⫾ 1.02 ⬍0.001 132 ⫾ 16 ⬍0.05
81 ⫾ 8 59.1 ⫾ 9.4
86 ⫾ 10 63.7 ⫾ 8.2
⬍0.05 NS
8.37 ⫾ 3.48 9.21 ⫾ 3.22 2.04 ⫾ 0.94 2.41 ⫾ 1.04
NS NS
89.0 ⫾ 11.8 92.8 ⫾ 7.2
NS
* Student’s t test for unpaired data. Values are shown as mean ⫾ SD. NS, not significant.
reia et al. (18), by leptin infusion into the intracerebral ventricle in rats, found that the hormone at pharmacological doses increased BP, at least in part through sympathetic nervous system activation. In epidemiological studies in humans, discordant results have been obtained in different populations depending on age, gender, and the inclusion of hypertensive patients. Takizawa et al. (32) carried out a study of 133 men and 238 women; in the female group no correlation was observed between leptin and BP, whereas a significant association was found in men. The relationship was independent of insulin resistance, but no data were available on fat distribution. In the population examined by Suter et al. (33), no association was found between leptin and BP; however, the authors reported a positive relationship on separate analysis of the women subgroup, as well as of normotensive men. In studies that described an association between leptin and BP, most often this appeared to be dependent on total fat mass. A BMI-dependent relationship between leptin and BP was found by Masuo et al. in a sample of Japanese men (34); on the other hand, the same authors failed to demonstrate a decrease in leptin levels during the BP fall associated with weight loss (35). According to Hu et al. (20), in a rural Chinese population sample, the association between BP and leptin was heavily influenced by body fat mass and distribution. Several authors found higher plasma leptin concentrations only within a cluster of several risk factors, includOBESITY RESEARCH Vol. 11 No. 1 January 2003
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Figure 2: The probability of being hypertensive increases across tertiles of log-leptin distribution, controlling both for age and waist circumference (A) and for age and BMI (B). *p ⬍ 0.05.
ing BP (27,36,37). Lindgarde et al. (21) reported the occurrence of high leptin levels in Swedish overweight women with high BP and low leptin in overweight Peruvian women with low BP. Finally, several studies in hypertensive patients reported the finding of high plasma leptin levels (22,23), but the confounding influence of overweight could not be ruled out. According to Uckaya et al. (38), plasma leptin was higher in hypertensive patients, but a continuous relationship between leptin and BP was not detected. The present study provides novel information on the relationship between circulating plasma leptin concentration and BP through the investigation of a large random sample of untreated male participants of the Olivetti Heart Study. It shows a graded, statistically significant, and clinically relevant association between plasma leptin concentration and BP that is largely independent of body mass and of abdominal adiposity. In particular, by comparing overweight individuals with individuals with high or low plasma leptin levels, but similar age, body mass, and degree of abdominal adiposity, it was possible to demonstrate that elevated plasma leptin was independently associated with higher systolic and diastolic BP. Furthermore, it was found that men with higher plasma leptin levels had significantly greater probability of being hypertensive, accounting for differences in age, total adiposity, and fat distribution. The association between leptin and BP was not dependent on insulin levels or insulin resistance estimated by the HOMA index. This study may not prove that this statistical association is the expression of a cause– effect relationship. Nevertheless, the finding that for similar levels of adiposity the higher the plasma leptin the higher the blood pressure is intriguing. Elevated levels of plasma leptin in the presence of excess adiposity and particularly of central adiposity are thought to reflect a condition of “leptin resistance,” charac164
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terized by the inability of leptin to promote a reduction in body fat accumulation. At present, it is not known whether resistance to the physiological effect of leptin on visceral fat is matched by resistance to the other peripheral effects of the hormone (7,39 – 42). Leptin is known to stimulate sympathetic activity within the vascular and the renal districts (7). In our study, there was a trend for a higher pulse rate, an approximate index of interindividual differences in sympathetic tone, in overweight individuals with higher vs. those with lower plasma leptin levels, but the difference did not achieve statistical significance. A limitation of our study is that it examined only a sample of white adult men; thus, its results cannot be extrapolated to other strata of the population, and in particular, to women. In relation to substantial differences in body fat distribution with prevalence of peripheral rather than central fat deposition (43), women show, in general, higher plasma leptin levels in comparison with men (23,44). Some studies suggest an association between leptin and BP (20), even independently of BMI (21), but other studies do not (32), and thus, this issue is as controversial in women as it is in men. Although our study did not investigate the influence of dietary habits on circulating leptin levels, both the urinary sodium excretion rate and the fractional excretion of sodium in the morning timed urine collection, which provide a gross estimate of dietary sodium intake, were not associated with plasma leptin (r ⫽ 0.010 and r ⫽ 0.013, respectively). Moreover, no significant differences in plasma leptin were observed between drinkers and nondrinkers (log-leptin: 0.52 ⫾ 0.28 and 0.57 ⫾ 0.27, respectively, p ⫽ 0.36), as well as between those who reported to practice regular exercise vs. those who did not (log-leptin: 0.48 ⫾ 0.28 and 0.53 ⫾ 0.27, respectively, p ⫽ 0.13). In conclusion, our study showed a graded positive relationship between plasma leptin levels and BP in untreated
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men. This association was independent of age, body mass, abdominal adiposity, fasting plasma insulin, and serum creatinine levels. The study also showed that elevated plasma leptin concentration was associated with substantially greater probability of hypertension, again independently of potential confounders. These results may contribute to the understanding of the mechanistic pathways linking overweight and abdominal adiposity to high BP and are relevant to the prevention of the cardiovascular complications of this epidemic metabolic alteration.
Acknowledgments This study was supported in part by grants from MURST (Italian Ministry of University and of Scientific and Technological Research COFIN 1998 and 2000) and by Modinform s.p.a. (Olivetti group). The authors are grateful to Umberto Candura, Antonio Scottoni, and Maria Bartolomei, in charge of the Olivetti factory medical center, for their valuable collaboration in the organization of the study in the field. They also thank the Olivetti employees for their enthusiastic participation. The excellent cooperation of Eliana Ragone, Luisa Russo, and Francesco Stinga in their work in the field is gratefully recognized. The editorial assistance of Rosanna Scala and Grazia Fanara is also gratefully acknowledged. References 1. Kannel WB, Brand N, Skinner JJJ, et al. The relation of adiposity to blood pressure and development of hypertension. The Framingham Study. Ann Intern Med. 1967;67:48 –59. 2. Stamler R, Stamler J, Riedlinger WF, et al. Weight and blood pressure. Findings in hypertension screening of 1 million Americans. JAMA. 1978;240:1607–10. 3. Mark AL. The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure. J Hypertens Suppl. 1996;14:S159 –S65. 4. Landsberg L. Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). J Hypertens. 2001; 19:523– 8. 5. Hall JE, Hildebrandt DA, Kuo J. Obesity hypertension: role of leptin and sympathetic nervous system. Am J Hypertens. 2001;14:103S–15S. 6. Friedman JM. Obesity in the new millennium. Nature. 2000; 404:632– 4. 7. Haynes WG, Sivitz WI, Morgan DA, et al. Sympathetic and cardiorenal actions of leptin. Hypertension. 1997;30:619 –23. 8. Narkiewicz K, Somers VK, Mos L, et al. An independent relationship between plasma leptin and heart rate in untreated patients with essential hypertension. J Hypertens. 1999;17: 245–9. 9. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998;31:409 –14. 10. Mark AL, Shaffer RA, Correia ML, et al. Contrasting blood pressure effects of obesity in leptin-deficient ob/ob mice and agouti yellow obese mice. J Hypertens. 1999;17:1949 –53.
11. Aizawa-Abe M, Ogawa Y, Masuzaki H, et al. Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest. 2000;105:1243–52. 12. Paolisso G, Tagliamonte MR, Galderisi M, et al. Plasma leptin concentration, insulin sensitivity, and 24-hour ambulatory blood pressure and left ventricular geometry. Am J Hypertens. 2001;14:114 –20. 13. Narkiewicz K, Kato M, Phillips BG, et al. Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects. J Hypertens. 2001;19:1089 –94. 14. Winnicki M, Phillips BG, Accurso V, et al. Independent association between plasma leptin levels and heart rate in heart transplant recipients. Circulation. 2001;104:384 – 6. 15. Strazzullo P, Iacone R, Siani A, et al. Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central adiposity and high blood pressure: interaction with age. Cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study. J Hypertens. 2001;19:399 – 406. 16. Cappuccio FP, Strazzullo P, Farinaro E, et al. Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA. 1993;270:354 –9. 17. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9. 18. Correia ML, Morgan DA, Sivitz WI, et al. Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure. Hypertension. 2001;37:936 – 42. 19. Sheu WH, Lee WJ, Chen YT. High plasma leptin concentrations in hypertensive men but not in hypertensive women. J Hypertens. 1999;17:1289 –95. 20. Hu FB, Chen C, Wang B, et al. Leptin concentrations in relation to overall adiposity, fat distribution, and blood pressure in a rural Chinese population. Int J Obes Relat Metab Disord. 2001;25:121–5. 21. Lindgarde F, Soderberg S, Olsson T, et al. Overweight is associated with lower serum leptin in Peruvian Indian than in Caucasian women: a dissociation contributing to low blood pressure? Metabolism. 2001;50:325–9. 22. Makris TK, Stavroulakis GA, Krespi PG, et al. Elevated plasma immunoreactive leptin levels preexist in healthy offspring of patients with essential hypertension. Am Heart J. 1999;138:922–5. 23. Mallamaci F, Cuzzola F, Tripepi G, et al. Gender-dependent differences in plasma leptin in essential hypertension. Am J Hypertens. 2000;13:914 –20. 24. Masuo K, Mikami H, Ogihara T, et al. Weight gain-induced blood pressure elevation. Hypertension. 2000;35:1135– 40. 25. Sanchez-Rodriguez M, Garcia-Sanchez A, Retana-Ugalde R, et al. Serum leptin levels and blood pressure in the overweight elderly. Arch Med Res. 2000;31:425– 8. 26. Corica F, Corsonello A, Ientile R, et al. Leptin and norepinephrine plasma concentrations during glucose loading in normotensive and hypertensive obese women. Am J Hypertens. 2001;14:619 –26. 27. Hodge AM, Boyko EJ, Courten M, et al. Leptin and other components of the Metabolic Syndrome in Mauritius-a factor analysis. Int J Obes Relat Metab Disord. 2001;25:126 –31. OBESITY RESEARCH Vol. 11 No. 1 January 2003
165
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28. Kuo JJ, Jones OB, Hall JE. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension. 2001;37:670 – 6. 29. Jackson EK, Li P. Human leptin has natriuretic activity in the rat. Am J Physiol. 1997;272:F333–F8. 30. Haynes WG, Morgan DA, Walsh SA, et al. Cardiovascular consequences of obesity: role of leptin. Clin Exp Pharmacol Physiol. 1998;25:65–9. 31. Haynes WG. Interaction between leptin and sympathetic nervous system in hypertension. Curr Hypertens Rep. 2000;2:311– 8. 32. Takizawa H, Ura N, Saitoh S, et al. Gender difference in the relationships among hyperleptinemia, hyperinsulinemia, and hypertension. Clin Exp Hypertens. 2001;23:357– 68. 33. Suter PM, Locher R, Hasler E, et al. Is there a role for the ob gene product leptin in essential hypertension? Am J Hypertens. 1998;11:1305–11. 34. Masuo K, Mikami H, Itoh M, et al. Sympathetic activity and body mass index contribute to blood pressure levels. Hypertens Res. 2000;23:303–10. 35. Masuo K, Mikami H, Ogihara T, et al. Differences in mechanisms between weight loss-sensitive and -resistant blood pressure reduction in obese subjects. Hypertens Res. 2001;24:371– 6. 36. Shmulewitz D, Auerbach SB, Lehner T, et al. Epidemiology and factor analysis of obesity, type II diabetes, hypertension, and dyslipidemia (syndrome X) on the Island of Kosrae, Federated States of Micronesia. Hum Hered. 2001;51:8 –19.
166
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37. Haffner SM, Mykkanen L, Rainwater DL, Karhapaa P, Laakso M. Is leptin concentration associated with the insulin resistance syndrome in nondiabetic men? Obes Res. 1999;7: 164 –9. 38. Uckaya G, Ozata M, Sonmez A, et al. Plasma leptin levels strongly correlate with plasma renin activity in patients with essential hypertension. Horm Metab Res. 1999;31:435– 8. 39. Bray GA. Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. Int J Obes Relat Metab Disord. 2000;24(Suppl 2):S8 –S17. 40. Ghorbani M, Himms-Hagen J. Treatment with CL 316, 243, a beta 3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity. Int J Obes Relat Metab Disord. 1998;22:63–5. 41. Haynes WG, Morgan DA, Walsh SA, et al. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997;100:270 – 8. 42. Tanida M, Iwashita S, Ootsuka Y, et al. Leptin injection into white adipose tissue elevates renal sympathetic nerve activity dose-dependently through the afferent nerves pathway in rats. Neurosci Lett. 2000;293:107–10. 43. Bjo¨rntorp P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition. 1997;13:795– 803. 44. Isidori AM, Strollo F, More M, et al. Leptin and aging: correlation with endocrine changes in male and female healthy adult populations of different body weights. J Clin Endocrinol Metab. 2000;85:1954 – 62.
