Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2015;68:672-9 - Vol. 68 Num.08 DOI: 10.1016/j.rec.2014.08.015

Leptin Reference Values and Cutoffs for Identifying Cardiometabolic Abnormalities in the Spanish Population

Teresa Gijón-Conde a,b,, Auxiliadora Graciani b, Pilar Guallar-Castillón b, M. Teresa Aguilera c, Fernando Rodríguez-Artalejo b, José R. Banegas b

a Centro de Salud Universitario Cerro del Aire, Majadahonda, Madrid, Spain
b Departamento de Medicina Preventiva y Salud Pública, Universidad Autónoma de Madrid/Idi Paz, CIBER de Epidemiología y Salud Pública CIBERESP, Madrid, Spain
c Departamento Médico, Sanofi-Aventis, Barcelona, Spain

Keywords

Leptin. Obesity. Cardiovascular risk factors. Cardiometabolic abnormality.

Abstract

Introduction and objectives

Estimate leptin reference values and calculate leptinemia cutoff values for identifying cardiometabolic abnormalities in Spain.

Methods

Cross-sectional study carried out between 2008 and 2010 in 11 540 individuals representing the Spanish population aged ≥ 18 years. Data were obtained by standardized physical examination and analyses were performed at a central laboratory. Leptinemia was measured using ELISA. Cardiometabolic abnormality was defined as the presence of at least two of the following: high blood pressure, high triglycerides, reduced high density lipoprotein cholesterol, high insulin resistance values, and elevated C-reactive protein and glucose.

Results

Leptin values were higher in women than men (geometric mean, 21.9 and 6.6 ng/mL; P < .001). The median [interquartile range] was 24.5 [14.1-37.0] ng/mL in women, and 7.2 [3.3-14.3] ng/mL in men. In the multivariate analysis, leptin was significantly associated with anthropometric measures, insulin, and C-reactive protein, and inversely associated with age, smoking, and physical activity in women (r2 = 0.53; P < .001) and in men (r2 = 0.61; P < .001). The leptin values that identified cardiometabolic abnormality were 23.75 ng/mL in women (area under the curve, 0.722; sensitivity, 72.3%; specificity, 58.7%) and 6.45 ng/mL in men (area under the curve, 0.716; sensitivity, 71.4%; specificity, 60.2%).

Conclusions

These results facilitate the interpretation of leptin values in clinical and population studies. Leptin has moderate sensitivity and specificity for identifying cardiometabolic abnormalities.

Article

INTRODUCTION

Leptin, a peptide described in 1994, is synthesized by adipocytes, and its serum concentration reflects the body's energy reservoir1. Leptin acts on the hypothalamic receptors and influences the expression of different neuropeptides that regulate energy balance by decreasing food intake and increasing energy expenditure and sympathetic tone in response to normal weight gain1.

Traditionally, body mass index (BMI) has been used to assess the degree of obesity. However, BMI has limitations in detecting adiposity in individuals with BMI < 302, 3, 4; recent studies have highlighted the usefulness of leptin for improving the accuracy of BMI in assessing the percentage of body fat when dual-energy X-ray absorptiometry (DXA) is not available, and may represent a future marker for obesity.5 The association between leptin and hypertension has also been studied,6, 7 and it has been suggested that it may activate the sympathetic nervous system, increasing blood pressure8, 9 or even increasing risk of hypertension.10, 11, 12 Leptin has also been found to be related to biological cardiovascular risk factors13 and to the development of cardiovascular disease.14, 15, 16, 17, 18, 19, 20 Finally, it has been reported that consumption of fiber and vegetables, physical activity, and smoking are inversely associated with leptinemia.21, 22, 23, 24

There are few population-based studies, particularly in samples of a reasonable size and representing entire countries, on the link between leptin concentrations and obesity and other cardiovascular risk factors.14, 15, 16, 25, 26, 27, 28, 29, 30, 31, 32 This information could be relevant for more precise estimates of fat mass and its potential role in mediating cardiometabolic risk. Moreover, there are no studies that explore the ability of leptin to predict cardiometabolic abnormality. Therefore, the aim of this study was to estimate the leptin reference values and calculate leptinemia cutoff values for identifying cardiometabolic abnormalities in women and men from the general population of Spain.

PARTICIPANTS AND METHODS

Data were obtained from The Nutrition and Cardiovascular Risk in Spain Study, the methodology of which was previously described.33 In brief, the study was conducted between June 2008 and October 2010, and included 12 948 people representing the noninstitutionalized Spanish population aged ≥ 18 years. Participants were selected by stratified cluster sampling. Data on sociodemographic and lifestyle variables were collected via telephone interview, and personal interviews, physical examinations, and collection of blood and urine samples were performed during two home visits. Data collection staff received training in the study's procedures.

Written informed consent was obtained from all participants. The study was approved by the Clinical Research Ethics Committees of Hospital Universitario La Paz (Madrid), and Hospital Clinic (Barcelona).

Study Variables

We used reported data on age, sex, educational level, smoking and diagnosed morbidity. In addition, we obtained a computerized dietary history on normal food consumption during the previous year, and calculated the number of kcal/day and the Healthy Eating Index (HEI).34 The following cutoff points were considered: poor diet (< 59.5), adequate (59.5-63.7), good (63.8-65.5), very good (65.6-67.5) and excellent (> 67.5).

Physical activity was measured using the EPIC Study questionnaire, which combines physical activity at work and during leisure time (Cambridge index).35 This index has been shown to accurately estimate cardiovascular risk and all-cause mortality.36 We also evaluated compliance with physical activity guidelines from the European Union and the World Health Organization (EU/WHO)37, which recommend ≥ 2.5 hours of moderate intensity activity or ≥ 1 hour of vigorous intensity activity per week.

We measured each individual's weight, height, and waist circumference using electronic scales (Seca 841; precision, 0.1 kg), portable extendable stadiometers (KaWe44 444Seca), and non-elastic flexible measuring tapes with buckles, respectively. Blood pressure was measured using validated automatic devices (Omron Model M6) according to standard procedures.38

Samples of blood and urine were obtained from each participant at home after 12 hours fasting. We measured glucose, C-reactive protein (CRP), glycosylated hemoglobin (HbA1c), insulin, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), which was calculated using Friedewald formula. Serum leptin was measured by enzyme immunoassay using two monoclonal antibodies (DBC, Diagnosis Biochem Canada, Inc.), automated using a BEST2000 robot. The sensitivity of this test was 0.5 ng/mL, and the intra- and inter-assay variation coefficients were 7.47% and 9.6%, respectively. These analyses were carried out using standardized methods at a central laboratory.

Cardiovascular Risk Factors

The BMI was calculated as weight in kilos divided by the square of height in meters. Abdominal obesity was defined as waist circumference > 102 cm in men and > 88 cm in women. Hypertension was defined as blood pressure ≥ 140/90 mmHg or if the patient was taking antihypertensive medication; diabetes mellitus as casual blood glucose ≥ 126 mg/dL, HbA1c ≥ 6.5%, or treatment with oral antidiabetic agents or insulin; hyperlipidemia as LDL-C ≥ 115 mg/dL or lipid-lowering drug treatment, and smoking as any level of tobacco consumption.

According to the harmonized definition,39 the diagnosis of metabolic syndrome requires meeting at least 3 of the following 5 criteria: waist circumference ≥ 102 cm for men and ≥ 88 cm for women; fasting glucose ≥ 100 mg/dL; blood pressure ≥ 130/85 mmHg; triglycerides ≥ 150 mg/dL, and HDL-C < 40 mg/dL in men, and < 50 mg/dl in women. Insulin resistance was estimated using the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR)40 and the following formula: insulin (mU/mL) × (glucose [mg/dL]/405). Insulin resistance was defined as HOMA-IR ≥ the 75th percentile (p75) and high leptin as ≥ p75 in our sex-stratified population, as in previous studies.20

Cardiometabolic abnormality was defined as the presence of 2 or more of the following: high blood pressure (systolic ≥ 130 and/or diastolic ≥ 85 mmHg or undergoing antihypertensive treatment); high triglycerides (≥ 150 mg/dL); low HDL-C (< 40 mg/dL in men and < 50 mg/dL in women or undergoing lipid-lowering therapy); high glucose (≥ 100 mg/dL or antidiabetic treatment); insulin resistance (HOMA-IR > 4.05, p90) and elevated CRP (> 0.74 mg/dL, p90).41

Statistical Analysis

Analyses were performed in 11 540 participants with complete data for all variables. The normality of the variables studied was verified by performing logarithmic transformation for leptin, triglycerides, insulin, PCR, and HOMA-IR, due to their skewed distributions.

Leptin levels were expressed as the geometric mean (standard deviation) the standard error of the mean and percentiles. We used the Student-Fisher t-test to compare means, and the chi-square test to compare proportions.

We used multiple linear regression to perform a multivariate analysis including age, BMI, waist circumference, blood pressure, glucose, cholesterol, log-triglycerides, HDL-C, LDL-C, fibrinogen, log-insulin, log-CRP, log-HOMA-IR, tobacco consumption, food intake (kcal/day), HEI, and the Cambridge index of physical activity. Variables were selected from the results of the bivariate analysis.

Receiver Operating Characteristic (ROC) curves were constructed to assess the ability of leptin to identify cardiometabolic abnormalities and metabolic syndrome by calculating the area under the curve and the 95% confidence intervals (95% CI); leptin values with highest sensitivity and specificity, and their 95% CI, are indicated.

Analyses were performed separately in men and women. Individual observations were weighted to represent the Spanish population. We considered P < .05 as the threshold of statistical significance. All analyses were performed using SPSS v19.0.

RESULTS

The main demographic and clinical characteristics of the study participants are shown in Table 1.

Table 1. General Characteristics of the Sample

  Total (n = 11 540) Women (n = 5823) Men (n = 5717)
Age, mean (SD), y 46.9 (17) 47.9 (17.4) 45.8 (16.8)
18-44 years 50.2 47.7 52.9
45-64 years 29.7 29.7 29.6
> 65 years 20.1 22.7 17.4
University education 28.2 27.2 29.3
Smoking
Ex-smokers 24.6 18.1 31.1
Current smokers 27.6 24.9 30.3
Cigarettes/day, n 14.5 13.1 15.8
Compliance with physical activity recommendations 57.2 47.9 66.6
Cambridge index, mean (SD) 2.27 (1) 2.07 (0.9) 2.47 (1.1)
Kcal/day 2181 1928 2438
Healthy Eating Index, mean (SD) 62.1 (12.7) 64.6 (12.3) 59.6 (12.8)
BMI, mean (SD) 26.9 (4.7) 26.3 (5.2) 27.4 (4.1)
Waist circumference, mean (SD), cm 90.8 (13.9) 85.3 (13.4) 96.2 (12.1)
SBP, mean (SD), mmHg 129.2 (17.9) 124.5 (18.4) 134 (15.9)
DBP, mean (SD), mmHg 75.8 (10.1) 73.9 (9.5) 77.7 (10.4)
Glucose, mean (SD), mg/dL 93.3 (21) 91.8 (19.7) 95 (22)
Total cholesterol, mean (SD), mg/dL 196.2 (38) 198.6 (37) 194 (38.6)
Triglycerides, mean (SD), mg/dL 112.6 (81) 97.3 (58) 126 (95)
HDL-C, mean (SD), mg/dL 53 (14.2) 59 (14) 46.8 (11)
LDL-C, mean (SD), mg/dL 121.1 (31.7) 120 (31) 122 (32)
CRP, mean (SD), mg/dL 0.13 (0.02) 0.13 (0.03) 0.12 (0.03)
Insulin, mean (SD), mU/mL 9.3 (7.5) 8.9 (7) 9.6 (8)
HOMA-IR 2.25 2.13 2.18
General obesity 22.6 20.9 24.3
Abdominal obesity 35.2 38.7 31.7
Diabetes mellitus 6.8 5.6 8
Hyperlipidemia 50.6 52.5 48.7
Hypertension 32.9 27.7 38.2
Metabolic syndrome 19.2 16.7 21.7
Cardiometabolic abnormality 40.5 33.6 47.6

BMI, body mass index; CRP, C-reactive protein; DBP, diastolic blood pressure; HDL-C, high density lipoprotein cholesterol; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; LDL-C, low density lipoprotein cholesterol; SBP, systolic blood pressure: SD, standard deviation.
Unless otherwise indicated, values are expressed as mean (standard deviation) or percentages.

Leptin concentrations were approximately 3 times higher in women than in men (geometric mean 21.9 and 6.6 ng/mL, respectively) and increased with increasing BMI and age (Table 2); the median was 24.5 [14.1-37.0] ng/mL in women and 7.2 [3.3-14.3] ng/mL in men. Mean leptin in men for each age group was as follows: 18-44 years, 5.2 ng/mL; 45-64 years, 8.1 ng/mL, and ≥ 65 years, 9.4 ng/mL. For women, the values were 18.7 ng/mL, 23.1 ng/mL, and 28.4 ng/ml, respectively.

Table 2. Leptin Values by Age, Sex, and BMI in Spain

  Leptin, mean (SD), ng/dL Percentiles
    5 10 25 50 75 90 95
Age (n)
Women (5823) 21.9 (0.25) 5.30 8.20 14.10 24.50 37.00 49.50 57.40
< 20 years (148) 20.13 (1.24) 5.10 7.80 13.90 21.22 35.71 44.58 50.65
20-29 years (892) 19.27 (0.61) 4.90 7.20 12.10 20.80 32.00 43.70 50.80
30-39 years (969) 17.58 (0.55) 3.94 6.00 10.60 19.30 31.50 45.20 53.01
40-49 years (1255) 20.25 (0.54) 5.00 7.80 13.00 22.70 33.60 46.99 54.20
50-59 years (874) 23.25 (0.65) 6.18 9.23 15.51 26.00 38.10 47.91 56.00
60-69 years (923) 26.56 (2.06) 8.31 11.40 12.29 30.37 41.50 51.43 62.26
70-79 years (631) 29.77 (0.97) 7.50 12.00 20.00 32.30 48.30 58.60 100.62
≥ 80 years (131) 25.55 (2.06) 5.20 9.09 17.34 31.17 42.40 57.69 101.17
Men (5717) 6.6 (0.12) 1 1.3 3.3 7.2 14.3 23 28.4
< 20 years (173) 2.94 (0.57) 0.99 0.99 1.00 2.20 7.00 17.20 21.73
20-29 years (997) 4.17 (0.26) 0.99 0.99 1.50 4.10 10.00 18.20 24.31
30-39 years (1032) 5.93 (0.29) 1.00 1.10 3.00 6.50 13.10 21.10 27.19
40-49 years (1283) 6.95 (0.25) 1.00 1.70 4.00 7.10 14.20 22.00 26.60
50-59 years (826) 7.90 (0.32) 1.50 2.30 4.70 8.40 15.22 24.29 28.90
60-69 years (864) 9.14 (0.34) 1.70 2.70 5.50 10.20 17.30 26.00 33.50
70-79 years (430) 9.33 (0.52) 2.00 2.40 5.11 10.33 17.78 27.01 37.47
≥ 80 years (111) 9.73 (1.20) 1.06 2.25 5.00 11.97 22.19 30.23 45.78
IMC (n)
Women
< 18.5 (112) 7.07 (0.72) 1.00 2.00 4.13 8.40 13.27 19.68 22.26
18.5-24.9 (2585) 14.09 (0.22) 3.60 5.41 9.70 15.70 23.31 31.00 36.00
25-29.9 (1892) 26.52 (0.33) 10.12 13.82 20.00 28.30 37.00 45.32 50.70
30-34.9 (873) 41.04 (0.69) 21.48 24.60 33.26 41.80 50.90 61.87 100.66
35-39.9 (264) 55.01 (1.59) 31.13 34.15 41.30 50.00 88.00 102.00 104.20
≥ 40 (97) 65.91 (2.79) 35.31 41.94 51.48 55.20 101.88 105.00 106.28
Men
< 18.5 (36) 1.44 (1.11) 0.99 0.99 0.99 1.00 1.50 8.09 20.61
18.5-24.9 (1592) 2.68 (0.11) 0.99 0.99 1.18 2.60 5.00 8.73 12.90
25-29.9 (2667) 7.26 (0.14) 1.80 2.50 4.50 7.60 12.80 18.70 23.20
30-34.9 (1137) 14.08 (0.28) 4.60 6.00 10.00 15.16 21.20 28.20 35.14
35-39.9 (243) 24.73 (0.85) 10.45 13.00 19.55 25.62 35.00 43.04 47.53
≥ 40 (42) 35.40 (2.28) 18.31 26.15 27.02 37.45 47.85 49.50 53.97

BMI, body mass index; SD, standard deviation.

Smokers were observed to have lower leptin levels than nonsmokers (9.55 compared to 13.98 ng/mL) (Table 3). Individuals with obesity (general and abdominal), hypertension, diabetes mellitus, hypercholesterolemia, and metabolic syndrome had higher leptin values than those with normal weight (P < .001). We observed no differences in leptin levels as a function of the diet quality index. Leptin was 40% lower in individuals who adhered to physical activity recommendations (P < .001).

Table 3. Leptin Values Stratified by Cardiovascular Risk Factors and Sex

  Total (n = 11 540) Women (n = 5823) Men (n = 5717) P
Smoking
Smokers 9.6 (0.26) 18.1 (0.44) 5.6 (0.21) < .001
Exsmokers 11.9 (0.30) 21.4 (0.61) 8.4 (0.23) < .001
Nonsmokers * 14.0 (0.26) 24.4 (0.36) 6.1 (0.19) < .001
Body mass index
Normal weight 7.4 (0.16) 13.8 (0.20) 2.7 (0.10) < .001
Overweight 12.5 (0.21) 26.6 (0.33) 7.3 (0.13) < .001
Obesity * 25.9 (0.46) 45.3 (0.67) 15.8 (0.30) < .001
Abdominal obesity
No 8.4 (0.14) 16.1 (0.21) 4.6 (0.10) < .001
Yes * 23.7 (0.33) 35.6 (0.46) 14.3 (0.25) < .001
Diabetes mellitus
No 11.8 (0.17) 21.5 (0.26) 6.3 (0.12) < .001
Yes * 16.4 (0.65) 29.6 (1.35) 10.7 (0.46) < .001
Hypertension
No 10.7 (0.18) 19.5 (0.26) 5.2 (0.13) < .001
Yes * 15.5 (0.33) 29.6 (0.58) 9.6 (0.22) < .001
Hypercholesterolemia
No 10.2 (0.23) 19.7 (0.37) 5.4 (0.17) < .001
Yes * 14.3 (0.24) 24.1 (0.36) 8.0 (0.17) < .001
Metabolic syndrome
No 10.6 (0.17) 19.8 (0.25) 5.4 (0.12) < .001
Yes * 20.9 (0.46) 36.5 (0.75) 15.5 (0.30) < .001
Diet quality
Poor 10.7 (0.26) 22.4 (0.48) 6.4 (0.18) < .001
Adequate 11.7 (0.47) 21.7 (0.74) 6.4 (0.33) < .001
Good 11.3 (0.73) 21.8 (1.19) 6.3 (0.51) < .001
Very good 11.7 (0.76) 20.1 (1.17) 6.2 (0.56) < .001
Excellent 14.1 (0.28) 21.9 (0.37) 6.9 (0.23) < .001
Physical activity (WHO recommendation)
No * 16.0 (0.27) 23.8 (0.37) 8.5 (0.24) < .001
Yes 9.8 (0.19) 20 (0.35) 5.7 (0.14) < .001

WHO, World Health Organization.
Values are expressed as geometric mean (standard error).

* P < .05.

The mean values of leptin in p75 were 14.3 ng/mL in men, and 37 ng/mL in women. The value of HOMA-IR in p75 was 2.64 (2.8 in men, 2.5 in women). The p75 of the CRP values was 0.34 mg/dL (0.30 mg/dL in men, 0.37 mg/dL in women).

Table 4 shows the results of the multivariate analysis using multiple linear regression for variables that were significantly and independently associated with log-leptin. The anthropometric measures, insulin, total cholesterol, and CRP were significantly and directly associated with leptin, whereas age, smoking, and physical activity showed significant inverse association with leptin in women (r2 = 0.53; P < .001) and men (r2 = 0.61; P < .001).

Table 4. Multiple Linear Regression Analysis Including Factors That Were Significantly and Independently Associated With Log-leptin in Women and Men

  β Standard Error P
Women
BMI 0.03 0.01 < .001
Log-insulin, mU/L 0.326 0.014 < .001
Log-CRP, mg/dL 0.052 0.006 < .001
Waist circumference, cm 0.003 0.000 < .001
Age, y –0.002 0.000 < .001
Smoking (non-smoker/smoker) 0.046 0.007 < .001
Physical activity index –0.19 0.003 < .001
Total cholesterol, mg/dL 0.001 0.000 < .001
Creatinine, mg/dL 0.113 0.023 < .001
Men
Waist circumference, cm 0.013 0.001 < .001
Log-insulin, mU/L 0.42 0.015 < .001
BMI 0.024 0.002 < .001
Physical activity index –0.034 0.004 < .001
Total cholesterol, mg/dL 0.001 0.000 < .001
Smoking (non-smoker/smoker) 0.058 0.008 < .001
Log-CRP, mg/dL 0.045 0.007 < .001
Age, y –0.001 0.000 < .001

BMI, body mass index; CRP, C-reactive protein.
Women, r2 = 0.53; men, r2 = 0.61.

Leptin tended to increase with increasing BMI, although 7.6% of men and 4.3% of women with BMI < 25 have high leptin (≥ p75) (Figure 1). Conversely, 80.3% of overweight men and 74.4% of overweight women, and 46.2% and 34.4% with mild obesity (BMI 30-34.9) had low leptin (<p75).

Prevalence of leptin >p75, stratified by BMI categories and sex. BMI, body mass index; p75, 75th percentile.

Figure 1. Prevalence of leptin >p75, stratified by BMI categories and sex. BMI, body mass index; p75, 75th percentile.

The ROC curve analysis showed that the leptin cutoff values to maximize sensitivity and specificity in identifying cardiometabolic abnormalities were 6.45 ng/ml in men (area under the curve, 0.716; sensitivity, 71.4%; 95%CI, 70.06%-73.74%; specificity, 60.2%, 95%CI, 58.82%-62.32%) and 23.75 ng/mL in women (area under the curve, 0.722; sensitivity, 72.3%; 95%CI, 70.40%-74.41%; specificity, 58.7%; 95%CI, 56.96%-60.07%) (Figure 2). We also calculated the leptin cutoff values that maximized sensitivity and specificity in identifying metabolic syndrome. In men these were 8.95 ng/mL (area under the curve, 0.768; 95%CI, 0.754-0.781), with 76.7% sensitivity and 65.7% specificity; in women they were 27.25 ng/mL (area under the curve, 0.748; 95%CI, 0.732-0.765) with 74.7% sensitivity and 62.7% specificity.

Leptin <i>receiver operating characteristics</i> curves for identifying cardiometabolic abnormalities in men and women. The leptin cutoff value that maximizes sensitivity and specificity is 6.45 ng/mL for men (area under the curve, 0.716; sensitivity, 71.4%; specificity, 60.2%) and 23.75 ng/mL for women (area under the curve, 0.722; sensitivity, 72.3; specificity, 58.7%). AUC, area under the curve.

Figure 2. Leptin receiver operating characteristics curves for identifying cardiometabolic abnormalities in men and women. The leptin cutoff value that maximizes sensitivity and specificity is 6.45 ng/mL for men (area under the curve, 0.716; sensitivity, 71.4%; specificity, 60.2%) and 23.75 ng/mL for women (area under the curve, 0.722; sensitivity, 72.3; specificity, 58.7%). AUC, area under the curve.

DISCUSSION

This is the first population-based study that provides data on leptin reference values representing an entire European country, which facilitates interpretation of leptin results in clinical and population studies. We observed significant differences in leptin levels between the sexes. Leptin was significantly and directly associated with anthropometric measures, insulin, total cholesterol and CRP, and inversely associated with age, smoking, and physical activity. Finally, leptin has moderate sensitivity and specificity for identifying cardiometabolic abnormality in both sexes.

The only national baseline studies have been conducted in the United States based on the National Health and Nutrition Examination Survey (NHANES). An analysis of NHANES 1988-199425 reported lower leptin values than our results, which may be due to the fact that these American data are from two decades ago, when the prevalence of obesity was lower than today. Nonetheless, Sierra-Johnson et al20 reported lower leptin values than the Spanish figures, using data from NHANES III study. They established values >p75 (>7.6 ng/dL in men, 23.6 ng/dL in women) as denoting “high leptin”; these values are also lower than those obtained for the same percentile in our study (14.3 ng/dL in men, 37 ng/dL in women). More recent studies in North America (1998-2009)5 reported higher mean leptin than in our study, which may be due to the increased prevalence of obesity in the United States. Moreover, these differences may be conditioned by ethnic differences, since leptin is higher in African American women and lower in Asian women27, 28, 29, 31.

To our knowledge, there are no published studies that explore the ability of leptin to identify cardiometabolic abnormality, and our results indicate that leptin might be useful for this. Recent studies in Spain have reported an association between leptin and other markers of inflammation and metabolic syndrome, diabetes mellitus and obesity42. The reported prevalence (40.5%) of cardiometabolic abnormality is approximately 20% higher than that of metabolic syndrome described in Spain,43 perhaps due to the inclusion of insulin resistance and CRP, which extend the criteria with respect to metabolic syndrome only.

Regarding its relationship with blood pressure, the available studies report that high levels of leptin are associated with blood pressure and the onset of hypertension.6, 7, 10, 11, 12 We observed a general association with hypertension in both sexes that was not maintained in the multivariate analysis, whereas other studies found this association only in men11 or only in women.44 These discrepancies could be explained by methodological differences and overfitting of the mathematical models that treat obesity as a confounder, when it may actually behave as an intermediate variable in the development of hypertension. Some authors suggest that only Mendelian randomization could demonstrate that leptin is a mediator of hypertension.45

Our results on the association between leptin and inflammatory markers of cardiovascular risk such as CRP and metabolic markers such as LDL-C and insulin resistance are consistent with those of previous studies.13, 27, 28 Note that, as with leptin, the degree of insulin resistance is higher in our population than in Asian populations.27, 28

In relation to diet, our data are consistent with NHANES III,46 where no relationship was observed between eating patterns and leptin, although leptin was higher in the group with the highest consumption of vegetables, where lower caloric intake was reported. As in this study, other studies have also indicated that leptin is inversely associated with smoking and physical activity.24, 47

The positive association between leptin and anthropometric measures, insulin, cholesterol, and CRP, and the inverse association with age and lifestyle variables such as smoking and physical activity are consistent with those described in previous population-based studies in different settings.25, 26, 27, 28

Like other studies in the general population, ours has some limitations. First, we excluded 11% of the sample when eliminating participants without complete information. Second, we may have underestimated leptin values, especially in older individuals, by excluding the institutionalized population, which is often older and has higher leptin. Moreover, as in other population surveys, we cannot rule out some selection bias, because the main reason for not participating in the study was the requirement to give blood. The overall survey response rate is among the highest in similar surveys carried out in Europe.48 Finally, we cannot rule out some selection bias due to the use of telephone surveys, although it is estimated that about 80% of the Spanish population have a landline.49

CONCLUSIONS

This study reports reference values for leptin in the general adult population in Spain. We observed much higher leptin in women than in men, and associations with various biological and lifestyle variables could help explain the variable behavior of obesity as a mediator of cardiovascular disease. Furthermore, the reasonable ability of leptin to predict cardiometabolic abnormality and metabolic syndrome in both sexes may be of interest for clinical practice as an indicator of overall cardiovascular risk.

FUNDING

Data for this analysis came from the ENRICA study, funded by Sanofi-Aventis.

This work was funded by grant FIS P113/02321 (Instituto de Salud Carlos III, Spain) and the Chair in Epidemiology and Control of Cardiovascular Risk, Universidad Autónoma de Madrid, Spain.

This study is led by an independent scientific committee.

CONFLICTS OF INTEREST

M.T. Aguilera is employed by Sanofi-Aventis; however, this company does not sell any products related to leptin and obesity.

Received 3 July 2014
Accepted 20 August 2014

Corresponding author: Centro de Salud Universitario Cerro del Aire, Avda. España 7, 28220 Majadahonda, Madrid, Spain. tgijon@salud.madrid.org

Bibliography

1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-32.
Medline
2. Romero-Corral A, Somers VK, Sierra-Johnson J, Thomas RJ, Collazo-Clavell ML, Korinek J, et al. Accuracy of body mass index in diagnosing obesity in the adult general population. Int J Obes (Lond). 2008;32:959-66.
3. Romero-Corral A, Montori VM, Somers VK, Korinek J, Thomas RJ, Allison TG, et al. Association of bodyweight with total mortality and with cardiovascular events in coronary artery disease: a systematic review of cohort studies. Lancet. 2006;368:666-78.
Medline
4. Franzosi MG. Should we continue to use BMI as a cardiovascular risk factor?. Lancet. 2006;368:624-5.
Medline
5. Shah NR, Braverman ER. Measuring adiposity in patients:the utility of body mass index (BMI), percent body fat and leptin. PLoSOne. 2012;7:e33308.
6. Grøntved A, Steene-Johannessen J, Kynde I, Franks PW, Helge JW, Froberg K, et al. Association between plasma leptin and blood pressure in two population-based samples of children and adolescents. J Hypertens. 2011;29:1093-100.
Medline
7. Shankar A, Xiao J. Positive relationship between plasma leptin level and hypertension. Hypertension. 2010;56:623-8.
Medline
8. Carlyle M, Jones OB, Kuo JJ, Hall JE. Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension. 2002;39:496-501.
Medline
9. Machleidt F, Simon P, Krapalis AF, Hallschmid M, Lehnert H, Sayk F. Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans. J Clin Endocrinol Metab. 2013;98:E491-6.
Medline
10. Kramer CK, Von Mühlen D, Barrett-Connor E. Does leptin predict incident hypertension in older adults?. Clin Endocrinol (Oxford). 2010;73:201-5.
11. Galletti F, D’Elia L, Barba G, Siani A, Cappuccio FP, Farinaro E, et al. High-circulating leptin levels are associated with greater risk of hypertension in men independently of body mass and insulin resistance: results of an eight-year follow-up study. J Clin Endocrinol Metab. 2008;93:3922-6.
Medline
12. Asferg C, Mogelvang R, Flyvbjerg A, Frystyk J, Jensen JS, Marott JL, et al. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. Am J Hypertens. 2010;23:327-33.
Medline
13. Wannamethee SG, Tchernova J, Whincup P, Lowe GD, Kelly A, Rumley A, et al. Plasma leptin: associations with metabolic, inflammatory and haemostatic risk factors for cardiovascular disease. Atherosclerosis. 2007;191:418-26.
Medline
14. Karakas M, Zierer A, Herder C, Baumert J, Meisinger C, Koenig W, et al. Leptin, adiponectin, their ratio and risk of Coronary Heart Disease: results from the MONICA/KORA Augsburg Study 1984-2002. Atherosclerosis. 2010;209:220-5.
Medline
15. Liu J, Butler KR, Buxbaum SG, Sung JH, Campbell BW, Taylor HA. Leptinemia and its association with stroke and coronary heart disease in the Jackson Heart Study. Clin Endocrinol (Oxford). 2010;72:32-7.
16. Lieb W, Sullivan LM, Harris TB, Roubenoff R, Benjamin EJ, Levy D, et al. Plasma leptin levels and incidence of heart failure, cardiovascular disease, and total mortality in elderly individuals. Diabetes Care. 2009;32:612-6.
Medline
17. Söderberg S, Stegmayr B, Stenlund H, Sjöström LG, Agren A, Johansson L, et al. Leptin, but not adiponectin, predicts stroke in males. J Intern Med. 2004;256:128-36.
Medline
18. Brennan AM, Li TY, Kelesidis I, Gavrila A, Hu FB, Mantzoros CS. Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study. Diabetologia. 2007;50:1178-85.
Medline
19. Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Obesity and risk of incident heart failure in older men with and without pre-existing coronary heart disease: does leptin have a role?. J Am Coll Cardiol. 2011;58:1870-7.
Medline
20. Sierra-Johnson J, Romero-Corral A, Lopez-Jimenez F, Gami AS, SertKuniyoshi FH, Wolk R, et al. Relation of increased leptin concentrations to history of myocardial infarction and stroke in the United States population. Am J Cardiol. 2007;100:234-9.
Medline
21. Murakami K, Sasaki S, Takahashi Y, Uenishi K, Yamasaki M, Hayabuchi H, et al. Nutrient and food intake in relation to serum leptin concentration among young Japanese women. Nutrition. 2007;23:461-8.
Medline
22. Chu NF, Stampfer MJ, Spiegelman D, Rifai N, Hotamisligil GS, Rimm EB. Dietary and lifestyle factors in relation to plasma leptin concentrations among normal weight and overweight men. Int J Obes Relat Metab Disord. 2001;25:106-14.
Medline
23. Ruige JB, Dekker JM, Blum WF, Stehouwer CD, Nijpels G, Mooy J, et al. Leptin and variables of body adiposity, energy balance and insulin resistance in a population-based study. The Hoorn Study. Diabetes Care. 1999;22:1097-104.
Medline
24. Franks PW, Farooqi IS, Luan J, Wong MY, Halsall I, O’Rahilly S, et al. Does physical activity energy expenditure explain the between-individual variation in plasma leptin concentrations after adjusting for differences in body composition?. J Clin Endocrinol Metab. 2003;88:3258-63.
Medline
25. Ruhl CE, Everhart JE, Ding J, Goodpaster BH, Kanaya AM, Simonsick EM, et al, Health, Aging, and Body Composition Study. Serum leptin concentrations and body adipose measures in older black and white adults. Am J Clin Nutr. 2004;80:576-83.
Medline
26. Ruhl CE, Everhart JE. Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr. 2001;74:295-301.
Medline
27. Zuo H, Shi Z, Yuan B, Dai Y, Wu G, Hussain A. Association between serum leptin concentrations and insulin resistance: a population-based study from China. PLoSOne. 2013;8:e54615.
28. Chiu FH, Chuang CH, Li WC, Weng YM, Fann WC, Lo HY, et al. The association of leptin and C-reactive protein with the cardiovascular risk factors and metabolic syndrome score in Taiwanese adults. Cardiovasc Diabetol. 2012;11-40.
29. Cohen SS, Fowke JH, Cai Q, Buchowski MS, Signorello LB, Hargreaves MK, et al. Differences in the association between serum leptin levels and body mass index in black and white women: a report from the Southern Community Cohort Study. Ann Nutr Metab. 2012;60:90-7.
Medline
30. Andreasson AN, Undén AL, Elofsson S, Brismar K. Leptin and adiponectin: distribution and associations with cardiovascular risk factors in men and women of the general population. Am J Hum Biol. 2012;24:595-601.
Medline
31. Khan UI, Wang D, Sowers MR, Mancuso P, Everson-Rose SA, Scherer PE, et al. Race-ethnic differences in adipokine levels: the Study of Women's Health Across the Nation (SWAN). Metabolism. 2012;61:1261-9.
Medline
32. Magni P, Liuzzi A, Ruscica M, Dozio E, Ferrario S, Bussi I, et al. Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin-sensitivity, lipid profile and macronutrient preference. Clin Endocrinol (Oxford). 2005;62:189-96.
33. Rodríguez-Artalejo F, Graciani A, Guallar-Castillón P, León-Muñoz LM, Zuluaga MC, López-García E, et al. Justificación y métodos del estudio sobre nutrición y riesgo cardiovascular en España (ENRICA). Rev Esp Cardiol. 2011;64:876-82.
Medline
34. Kennedy ET, Ohls J, Carlso S, Fleming K. The Healthy Eating Index: design and applications. J Am Diet Assoc. 1995;95:1103-8.
Medline
35. Wareham NJ, Jakes RW, Rennie KL, Schuit J, Mitchell J, Hennings S, et al. Validity and repeatability of a simple index derived from the short physical activity questionnaire used in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutr. 2003;6:407-13.
Medline
36. Khaw KT, Jakes R, Bingham S, Welch A, Luben R, Day N, et al. Work and leisure time physical activity assessed using a simple, pragmatic, validated questionnaire and incident cardiovascular disease and all-cause mortality in men and women: The European Prospective Investigation into Cancer in Norfolk prospective population study. Int J Epidemiol. 2006;35:1034-43.
Medline
37. EU Working Group “Sport and Health”. Bruxelles: EU Physical Activity Guidelines;2008.
38. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159-219.
Medline
39. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention;National Heart. Lung and Blood Institute;American Heart Association;World Heart Federation;International Atherosclerosis Society;and International Association for the Study of Obesity. Circulation. 2009;120:1640-5.
40. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Teacher DF, Turner RC. Homeostasis model assessment: insulin resistance and b cell function from fasting plasma glucose and insulin concentration in man. Diabetologia. 1985;28:412-9.
Medline
41. Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004). Arch Intern Med. 2008;168:1617-24.
Medline
42. Fernández-Bergés D, Consuegra-Sánchez L, Peñafiel J, Cabrera de León A, Vila J, Félix-Redondo FJ, et al. Perfil metabólico-inflamatorio en la transición obesidad, síndrome metabólico y diabetes mellitus en población mediterránea. Estudio DARIOS Inflamatorio. Rev Esp Cardiol. 2014;67:624-31.
43. Guallar-Castillón P, Pérez RF, López García E, León-Muñoz LM, Aguilera MT, Graciani A, et al. Magnitud y manejo del síndrome metabólico en España en 2008-2010: Estudio ENRICA. Rev Esp Cardiol. 2014;67:367-73.
Medline
44. Ma D, Feitosa MF, Wilk JB, Laramie JM, Yu K, Leiendecker-Foster C, et al. Leptin is associated with blood pressure and hypertension in women from the National Heart. Lung, and Blood Institute Family Heart Study. Hypertension. 2009;53:473-9.
Medline
45. Jeppesen J, Asferg C. Positive relationship between plasma leptin levels and hypertension from an epidemiological perspective. Hypertension. 2010;56:573-4.
Medline
46. Ganji V, Kafai MR, McCarthy E. Serum leptin concentrations are not related to dietary patterns but are related to sex, age, body mass index, serum triacylglycerol, serum insulin, and plasma glucose in the US population. Nutr Metab (London). 2009;14:6-13.
47. Donahue RP, Zimmet P, Bean JA, Decourten M, De Carlo Donahue RA, Collier G, et al. Cigarette smoking, alcohol use, and physical activity in relation to serum leptin levels in a multiethnic population: the Miami Community Health Study. Ann Epidemiol. 1999;9:108-13.
Medline
48. Aromaa A, Koponen P, Tafforeau J, Vermeire C, HIS/HES Core Group. Evaluation of health interview surveys and health examination surveys in the European Union. Eur J Public Health. 2003;13(3 Supl):67-72.
Medline
49. Encuesta sobre Equipamiento y Uso de Tecnologías de Información y Comunicación en los hogares 2010. Madrid: Instituto Nacional de Estadística [cited 30 Jul 2014]. Available at: http://www.ine.es/inebmenu/mnu_tic.htm.

1885-5857/© 2015 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

Cookies
x
To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.
Cookies policy
x
To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.